helicobacter pylori diagnosis, treatment and risks of ... · helicobacter pylori: diagnosis,...

Helicobacter pylori: Diagnosis, treatment and risks of untreated infection

bB

Klaus MönkemüllerDepartment of Gastroenterology, Hepatology

und Infectius DiseasesOtto-von-Guericke University, Magdeburg

InvasiveInvasive Non invasiveNon invasive

Rapid urease testRapid urease test 1313C/C/1414CC--breath testbreath test

HistologyHistology Stool antigenStool antigen

MicrobiologyMicrobiology SerologySerology (serum(serum, , blood)blood)

(FISH, PCR)(FISH, PCR) (Urine)(Urine)

Helicobacter pylori Diagnosis

Rapid urease testRapid urease test

•• SensitivitySensitivity / / SpecificitySpecificity > 90%> 90%

•• One biopsy from each antrumOne biopsy from each antrum & &

corpuscorpus

•• Cost effectiveCost effective

LabenzLabenz et al. Digestion 1999et al. Digestion 1999Malfertheiner et al. Malfertheiner et al. EurEur J J GastroentereolGastroentereol Hepatol 1996Hepatol 1996


Maastricht 3-2005

Level of Evidence: 2 Grade of Recommendation: A

Statement:In patients presenting for endoscopy without pre-treatment, a positive RUT is sufficient to initiate a therapy.

95,7

4,30

25

50

75

100

I agree I don't agreeValues in percentage

Urea breath test 13CO²

13C-labeled urea

urease

ammonia 13CO²13CO²

Urea blood test

PPI decrease sensitivity of UBT for detection of H. pylori

• 13C-UBT turned negative in 50% of patients after 5 days therapy with 80 mg of Omeprazole

• Stoschus B et al. Eur J Gastroenterol 1996

• Mechanism: unknown– Inhibits Hp growth– Reduces the concentration of bacteria– Decreased urea entrance into bacteria

• Available UBT and stool Ag tests become reliable only 2-6 weeks after stopping antibiotics + PPIs

.

False negative due to PPI is dependent on PPI

• 179 patients• PPI x 14 days, then UBT

– (high dosage citric acid 4 gm)False negatives

Omeprazole 20m g/d 4.1%Pantoprazole 40 mg /d 2.2%Lansoprazole 30 mg/d 16.6%Esomperazole 40 mg/d 13.6%

.Levine et al APT 2005

50%55%60%65%70%75%80%85%90%95%

100%

FemtoLabH. pylori

Cnx

PremierPlatinum

HpSA

UreaBreathTest

Serology

SensitivitySpecificity

Malfertheiner et al. Gut 2001

European European MulticenterMulticenter Study to compare various nonStudy to compare various non--invasive invasive methods for the diagnosis of methods for the diagnosis of H. pyloriH. pylori


Maastricht 3-2005

Level of Evidence: 1 Grade of Recommendation: B

Question: Which are the non-invasive tests to be used in the test and treat strategy?

Statement:

The non-invasive tests that can be used for the test and treat

strategy are UBT and the stool antigen tests. Certain kits for

serology with high accuracy can also be applied.

76,2

23,8

0

25

50

75

100


Maastricht 3-2005

Level of Evidence: 1 Grade of Recommendation: A

Statement:PPI is a source of false negative diagnostic tests except serology. PPI should be stopped for at least 2 weeksbefore performing the diagnostic test.

92,9

7,1

0

25

50

75

100


Evaluation of Evaluation of eradicationeradication

–– 1313CC--breath test breath test –– Stool antigenStool antigen--test test

94 9794

100

80

85

90

95

100

%

HpSA 13C-UBT

Sensitvity Specificity

Vaira et al. Ann Intern Med 2002


Maastricht 3-2005

Level of Evidence: 1b Grade of Recommendation: A

Statement:It is recommended to follow up patients after H. pylori eradication with UBT if available. If not available a laboratory-based stool test, preferably using monoclonalantibodies, could be used.

83,7

16,3

0

25

50

75

100


Maastricht 3-2005

• PPI Clarithromycin Amoxycillin2 x Stand. 2 x 500 mg 2 x1000 mg

(if clarithromycin resistance < 15%)

• PPI Clarithromycin Metronidazol2 x Stand. 2 x 500 mg 2 x 400 mg

(if metronidazole resistance , 40%)

• Bismuth based Quadruple Therapies

First line options

Duration of therapy: at least 7 days, max. 14 days

Primary clarithromycin resistance in Europe

% RESISTANCERESISTANCEMACH2 MACH2

Sweden, 1997 2.7Finland, 2004 2.0U.K., 2001-2004 4.4 - 7Ireland, 1996 4.5Germany, 1998-2001 2.0 - 4.9Belgium, 1992-1997 1.7 - 10.5France, 1997-2000 2.0 - 11.0Italy, 2000-2003 1.8 - 23.4 Spain, 1998 - 2000 5.7 - 6.2Bulgaria, 2004 11.9

Expected Eradication rates of PPI-CA and PPI -CM according to resistance rate to

Clarithromycin (C) and Metronidazole (M)

0

10

20

30

40

50

60

70

80

90

100

10 20 30 40 50

PPsCAPPsCM(M resistance 30%)PPsCM (M resistance 20%)PPsCM (M resistance 10%)

Megraud F. Current Infectious Disease Reports 2005

C resistance (%)

Era

dica

tion

(%)

Resistance acording to underlying diesease

0

5

10

15

20

25

30

35

%

Ulcer Gastritis Normal mucosa

MZ CLA MZ+CLA CIP

Patients not previously treated

Resinet, Professor Manfred Kist, Freiburg, Germany, Dec 2006

Smoking increases the therapeutic failure of H. pylori eradication

• Meta-Analysis: 22 Studies, 5538 patients• OR eradication failure: smoker versus

non-smoker: 1.95 (p<0.01)• Difference of eradication rates: 8.4%

Suzuki T et al. Am J Med 2006;119:217-24

Maastricht 3-2005

Level of Evidence: Grade of Recommendation:

Question: What is the recommended first line treatment?

Statement:•PPI – clarithromycin amoxicillin or metronidazole therapy remains the recommended first line therapy in populations with less than 15-20% clarithromycin resistance prevalence. In population with less than 40% metronidazole resistance prevalence PPI – clari – metro is preferable•Quadruple therapies are alternative first line therapies

94,6

5,4

0

25

50

75

100


Efficacy of short and long therapiesfor H.pylori infection

6%10-14 vs 7Quadruple

2%14 vs 10

3%10 vs 7

9% - 12%14 vs 7

Triple

Increase in cure rateDuration (days)Therapy

Calvet X et al. APT 2000;14:603-9Fishbach LA et al APT 2004;20:1071-82

Ford A. et al. Can J Gastroenterol 2003; 17: 36-40

CYP2C19 Polymorphisms

0102030405060708090

100

Eradication PPI level

mt/mtmt/wtwt/wt

Schwab et al Clin Pharmacol Ther 2004

Maastricht 3-2005

Evidence: 2 Grade of Recommendation: B

Results (%)

Question: Which one is the second line therapy of choice?

Statement:• Wismut-based quadruple therapies remain the bestsecond line therapy, if available. If not PPI amoxicillinor tetracyclin and metronidazole are recommended

90.2

9.8

0

25

50

75

100

I agree I don't agree

PPI, PPI, RifabutinRifabutin and and LevofloxacinLevofloxacin versus Quadruple versus Quadruple Therapy as Second Line TreatmentTherapy as Second Line Treatment

PPI,LRPPI,LR

Erad

icat

ion

rate

(%)

Erad

icat

ion

rate

(%)

PPI,BMTPPI,BMT

Wong, Aliment Wong, Aliment PharmacolPharmacol TherTher 2003, 17: 5532003, 17: 553--560560

0

20

40

60

80

100ITTITTPPPP

Reserve therapies (1)

1. PPI-AM-Therapy („Englishe Therapy“) (14 days)

PPI 2 x SD/Amoxicillin 2x1g/Metronidazol 2x400mg

2. High dose-dual therapy (14 days)PPI (3x SD), Amoxicillin 3x1g

3. Rifabutin-based therapy (7 days)PPI 2 x SD/Amoxicillin 2 x 1g/Rifabutin 2 x 150mg

4. Bismuth-based quadruplePPI-Standard dosage + Bismutsubcitrat (2 x 240 mg) Tetrazyclin (4 x 500 mg) + metronidazol ( 4 x 500 mg) or furazolidone* (2 x 200 mg) x 7 - 14 days

5. Gyrase inhibitor &Amoxicillin (7 days)PPI 2 x SD/Amoxicillin 2 x 1g/Levofloxacin 1 x 500 mg or Moxifloxacin 1 x 400 mg

6. Rifabutin & gyrase inhbitor (if Penicillin-Allergy)( 7 days)

PPI 2 x SD/Rifabutin 2 x 150mg/ 1 x 500 mg orMoxifloxacin 1 x 400 mg

Reserve therapies (2)

Maastricht 3-2005

Level of Evidence: 2c Grade of Recommendation: B

Statement:The rescue therapy should be based on

antimicrobial suseptibility testing

92,7

7,3

0

25

50

75

100


Development of Peptic Ulcer in NUD Patients

Placebo EradicationTherapy

Blum 4.0 % 0.6 %

Talley 5.0 % 0.2 %

Hsu 7.5 % 2.5 %

McColl 2.0 % 0 %Cochrane Library 2005

H. pylori H. pylori and and gastric cancergastric cancer

HpHp--AgAg

ILIL--8; 8; IL1IL1ββ

Macrophages

TT--helper helper cellscells

PMN

UreaseUreaseLPSLPS

CytotoxinCytotoxinVacAVacACagACagA

NONO

ROSROSIL1IL1ββ

↓ H+

↑ Atrophy

El Omar 2000El Omar 2000

Gastrin Gastrin ↑↑

SomatostatinSomatostatin ↓↓

Effects on gastric physiologyEffects on gastric physiology

H. pylori infection and gastric cancer: A prospective endoscopy study

•1526 patients with NUD, DU, GU or gastric hyperplasia (GH)

•Endoscopy: enrollment and every 1-3 years

•No antibiotic treatment

•Mean follow-up: 7.8 years

Uemura et al, N Engl J Med 2001; 345:784

Hp- Hp+ NUD GU GH DU 0

2.9

4.7

3.4

2.2

00

1

2

3

4

5Incidence of gastric cancer (%)

H. pylori Infection und stomach CAA prospective endoscopic studyUemuraUemura et al. N Eng J Med 2001et al. N Eng J Med 2001

Gastric Histology and cancer in non-ulcer dyspepsia

6.4 (2.6,16.1)6.5%464Intestinal metaplasia

4.9 (2.8-19.2)7.2%208Atrophy severe

1.7 (0.8-3.7)2.7%657Atrophy moderate

Relative risk

HP+ with gastric cancer n=36

NBaseline

Uemura N. New Engl J Med 2001;345:784-9

Impact of H. pylori infection on gastric cancer incidence

0

1

2

3

4

5

6

Hp+ Hp-

MaleFemale

731 Hp-

1171 Hp+Follow-up: 9 years

Relative risk of CA: 2.59 Yamagata Arch Int Med 2000

Maastricht 3-2005

Statement: H. pylori infection is the most common proven risk

factor for human non-cardia gastric cancer.

Level of Evidence: n.a. Grade of Recommendation: A

97,7

2,30

25

50

75

100


H. pylori, NSAID use, and risk of peptic ulcer disease: Meta-analysis of 5 case control

studies

Huang et al, Lancet 2002; 359:14-22

49.2

OR=2.8

OR=16.5

26OR=5.7

H. pylori -positive

5.5

0

80

Peptic ulcer (%)

n = 307 308 344 242

H. pylori -negative

Non-NSAID takers

25

NSAID takers

OR=5.99

Maastricht 3-2005

Level of Evidence : 1b Grade of Recommendation: A

Statement:H. pylori eradication is of value in chronic NSAID users but is insufficient to completely prevent NSAID-related ulcer disease

90,5

9,5

0

25

50

75

100


H. pylori und drug use; NSAIDs (and Cox2-Inhibitors)

Maastricht 3-2005

Level of Evidence: 1b Grade of Recommendation: A

Statement:Patients who are on long-term aspirin who bleed should be tested for H. pylori, and if positive receive eradication therapy.

H. pylori and drugs (aspirin)

93,5

6,5

0

25

50

75

100


Conclusions

• Best tests for the diagnosis of H. pylori: RUT, UBT, antigen stool test

• Triple therapy remains standard eradication strategy– Choose regimen based on resistance patterns in your area– 14 days increase eradication rates but are not cost-effective– Smoking decreases eradication rates

• Rescue therapies ( > 2) should be based on susceptibility testing (antibiogram)

• Untreated H. pylori infection will lead (varying %) to peptic ulcer, atrophic gastritis, intestinal metaplasia, gastric cancer, etc.

helicobacter pylori diagnosis, treatment and risks of ... · helicobacter pylori: diagnosis,...

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