HELICOBACTER PYLORI

1
HELICOBACTER PYLORI

• TREATMENT
• Georges El JAMMAL M.D.

2
Whom to treat ?

• Certainly gastro-duodenal ulcers

3
Whom to treat ?

• Dyspepsia
• Diagnostic gastroscopy recommended by all the
  experts before treatment in case of
• Age gt 45 years
• Risk factor for cancer
• History in favor of organic problems

4
Whom to treat ?

• Dyspepsia
• Test then treat (USA) or
• endoscopy then treat (europe) in case of
• Age lt 45 years
• No risk factor for cancer
• History in favor of functionnal problem

5
Whom to treat ?

• Dyspepsia
• Eradication yields a benefit in dyspepsia of less
  than 10 (Mc Coll et al. GUT 200148759-61)

6
Whom to treat ?

• Dyspepsia
• Conclusion Eradicate if
• Severe symptoms ?
• In the context of gastric cancer prevention ?
• (Raymond et al. Gastroenterol Clin Biol
  200327432-439)

7
Whom to treat ?

• GERD
• HP has a protector effect on the consequences of
  GERD ?
• Dent et al. Eur J Gastroenterol Gepatol 199911
  (suppl 2)S51-7
• Eradication does not increase the risk of
  esophagitis
• randomized trial with 18 weeks follow up Befrits
  et al. Helicobacter 20005202-5
• There is no relation between HP status and
  esophageal motor disorders
• Zerbib et al. Am J Physiol 2001281G350-6

8
Whom to treat ?

• GERD
• It cannot be recommended to eradicate HP in GERD
  unless it is needed for another indication
• European consensus conference on HP recommended
  eradication of HP before long term therapy for
  GERD
• Zerbib et al. Gastroenterol Clin Biol
  200327427-431

9
Whom to treat ?

• NSAID
• Gastroduodenal ulcers in NSAID patients
  Aggravated by HP ?
• Yes
• Bianchi-Poro et al. GUT 1996 39 22-6
• Taha et al. Gastroenterology 1999 116 254-8
• No
• Pilotto et al. Eur Gastroenterol Hepatol
  1997 9 951-6
• Bianchi-Poro et al. Digestive liver disease
  2000 32  201-8

10
Whom to treat ?

• NSAID
• Data apparied with age 
• HP increases risk of hemorragic GD ulcer x 1.79
• NSAID increases risk of hemorragic GD ulcer x
  4.85
• HP NSAID increases risk of hemorragic GD ulcer
  x 6.13
• Santolaria et al. Aliment Pharmacol Ther
  1999 13 1511-8

11
Whom to treat ?

• NSAID
• HP infection may retard healing of duodenal
  ulcers But may accelerate healing of gastric
  ulcers (Hawkey et al. GUT 2002 51 344-50)
• HP eradication before any NSAID prolonged therapy
  (Chan et al. Lancet 2002 359 9-13)
• gt Decreases ulcer induction by 65
• gt Decreases complicated ulcer induction by 85

12
Whom to treat ?

• NSAID
• In front of all these controversial or unclear
  data 
• ? Past history of GD ulcer ? test for HP and
  eradicate if positive
• ? No past history of GD ulcer 
• Eradication may be benefic before starting NSAID
• No clear recommendation could be made for
  patients already on NSAID
• (Thiefin gastroenterol Clin Biol
  2003 27 415-426)

13
First line treatment

• Triple drug therapy of one week
• PPI Am Cla
• Lind et al. The MACH I study. Helicobacter 1996
  1138-44
• Conference de consensus HP. Gastroenterol Clin
  Biol 199923C95-104
• Consensus report of Maastricht 2-2000

14
First line treatment

• ER before 1998 was gt 90
• ER after 1998 is less than 75
• France ?
• Laurent J et al. Aliment Pharmacol Ther 2001
  151787-93
• Tankovic J et al. Aliment Pharmacol Ther 2001
  15707-13
• Tchamgoue et al. Gastroenterol Cli Biol 2000
  24(suppl 2 bis)A138
• Delchier et al. Gastroenterol Clin Biol 2001
  25(suppl 2 bis)A8
• Italy ?
• Della et al. Aliment Pharmacol Ther
  2002161269-75
• UK ?
• Lee et al. Aliment Pharmacol Ther 199913489-96

15
First line treatmentBismuth

• Ranitidine-Bismuth-Citrate
• v/s
• Omeprazole
• RBC-Am-Cla Om-Am-Cla x 1W
• Gisbert et al. Aliment Pharmacol Ther
  2000141141-50

16
First line treatmentwhich PPI ?

• Triple therapy eradication based on 
• Om 20 mg Lan 30 mg Pa 40 mg Rb 20 mg
• Vaira et al. Curr Opin Gastroenterol
  1998 14(suppl 1) S71-8
• Megraud et al. Gastroenterol Clin North Am
  2000 29 759-73
• Qasim et al. Aliment Pharmacol Ther
  2002 16 suppl 1 24-30
• Suerbaum et al. N Engl J Med 2002 347 1175-86)
• Eso-om 20 bid om 20 bid
• Laine et al. Am J Gastroenterol 2000  95 3393-8
• Tenatoprazole 40 mg
• Canadian trial (Am J Gastroenterol. 2005
  Sep100(9)1949-56)

17
First line treatment Utility of PPI

• Acid suppression increases ATB diffusion
• Am-Cla ? ER 25 ? with PPI ? 94 1W
• Cla-Met ? ER 69 ? with PPI ? 87
  1W
• Lind et al. Gastroenterology 1999  116 248-53

18
First line treatmentDose of PPI ?

• Single dose ? ER 77.7
• Double dose ? ER 83.9
• Meta-analysis  (Vallve et al. Aliment Pharmacol
  Ther 2002 16 1149-56)
• Single dose PPI in the elderly ? acceptable
  results
• Pilotto et al. Aliment Pharmacol Ther
  200216683-91

19
First line treatmentDose of PPI ?

• Randomized study on 450 duodenal ulcer patients
  (Spain)
• gt PPI x 2 PPI x 4
• (Gisbert et al. Am J Gastroenterol. 2005
  Sep100(9)1935-40)
• Eso (20 mg bid) Cla (500 mg b.i.d.) Am (1 g
  b.i.d.) x 7 days
• ER () -----gt 74
• Eso (40 mg b.i.d.) Cla (500 mg b.i.d.) Am (1 g
  b.i.d.) x 7 days
• ER () -----gt 78
• Eso (40 mg b.i.d.) Cla (500 mg b.i.d.) Am (1 g
  b.i.d.) x 10 days
• ER () -----gt 80

20
First line treatmentHigh Dose PPI ?

• Randomized Controlled Trial on 323 patients with
  H. pylori (Manes et al. Dig Dis Sci. 2005
  Mar50(3)443-8) (Italy)
• Om 20 mg bid Om 40 mg bid
• even in cases of resistance
• Global ER
  ()
• Om 20 bid, Cla, Tinidazole 83.3
• Om 40 bid, Cla, Tinidazole 81.9

21
AntibioticsMetronidazole

• Geographic variation in response rate
• meta-analysis of 666 trials including 53228
  patients
• Met triple therapy
• Italy ? gt 90
• France ? lt 80
• Laheij et al. Aliment Pharmacol Ther
  199913857-64

22
AntibioticsMetronidazole resistance

• 36 in USA (Meyer et al. Ann Intern Med
  200213613-24)
• 44 in a france (Tankovic et al. Aliment
  Pharmacol Ther 200115707-13)
• 30 40 in UK (Parson et al. Aliment Pharmacol
  Ther 2001151473-8)
• 25 in germany (Wolle et al. J Med Microbiol
  200251705-9)
• 15 in Italy (Bazzoli et al. Gastroenterology
  2000118(suppl 2)A2652)

23
AntibioticsMetronidazole resistance

• ? PPI-Am-Cla ? efficacy independent of
  Metronidazole resistance
• ? could be eradicated by associating PPI-Cla-Met
  with 75 success rate but risk inducing double
  resistance
• ? no benefice with PPI-Am-Met
• Houben et al. Aliment Pharmacol
  Ther 1999131047-55
• ? increasing metronidazole doses is useless
• Metro 400 bid 400 tid 800 bid
• ER 57 for metro-resistant strains
• ER 87 for metro-sensible strains
• HOMER. Helicobacter 20005196-201

24
AntibioticsMetronidazole resistance

• Randomized Controlled Trial on 342 HP
• (Koivisto et al. Aliment Pharmacol Ther. 2005 Mar
  1521(6)773-82)

25
Clarithromycin dose

• 500 bid gt 250 bid
• (Cammarota etal. J Clin Gastroenterol. 2004
  Feb38(2)110-4)

26
Clarithromycine Clarithromycine resistance

• 10 in USA
• (Meyer et al. Ann Intern Med 200213613-24)
• 14 in France
• (Megraud et al. Gut 199843 suppl 1S61-5)
• 3-5 in UK
• (Parson et al. Aliment Pharmacol Ther
  2001151473-8)
• 5 in Germany
• (Lehmann et al. Aliment Pharmacol Ther
  200014305-9)

27
Clarithromycine Clarithromycine resistance

• Clarithro- resistant strains
• do not respond to PPI-Cla-Am
• nor to PPI-Met-Cla
• increasing Cla to 1500 mg/d ? little benefice
  but frequent side effects
• (Laheij et al. Aliment Pharmacol Ther
  199913857-64

28
Amoxicillin

• HP resistance to Amoxicillin
• is unusual

29
AntibioticsResistance

• Pilotto et al. Aliment Pharmacol Ther
  199913667-73

30
Antibiotics Tetracyclines

• La 30 bid Am 1g bid Tetracycline 500 qid x
  1W ? ER 35
• La 30 bid Am 1g bid- Doxicycline
  x 2W ? ER 36
• (Italian Study) Perri et al. Helicobacter
  2002799-104)
• ? no recommendation for its use

31
Antibiotics Azythromycine

• Variable results
• Az 500 od x 3 days PPI (La or Pa) Tinidazole
  ? ER 80
• (Cammarota et al. Eur J Gastroenterol
  Hepatol199911247-50)
• Az 500 bid x 3 days Pa Tinidazole ? ER 88
• (Calabrese et al. Aliment Pharmacol Ther
  2000141613-7)
• Az 500 bid Om 20 bid Am 1g bid ? ER 37.5
• (Laurent et al. Aliment Pharmacol Ther
  2001151787-93)

32
AntibioticsLevofloxacin

• Rab 20 mg bid Levofloxacin 500 mg o.d. Cla
  500 mg b.d. x 1 w ? 94 ER
• Randomized Controlled Trial on 100 HP patients
• (Cammarota etal. J Clin Gastroenterol. 2004
  Feb38(2)110-4)
• Levofloxacine 250 mg bid Am 1g bid Pa 40 bid
  x 10 d ? 70 eradication rate
• Randomized Controlled Trial (Bilardi C et al
  (Italy). Clin Gastroenterol Hepatol. 2004
  Nov2(11)997-1002)

33
AntibioticsOfloxacin

• Ofloxacin 400 mg bid in PPI-Am regimen  76
  dyspeptic patients
• 14 days ? ER 93
• 7 days ? 62.2
• ? no control group with Cla regimen
• ? 14 days regimen ? ?
• (Bosques et al. Helicobacter. 2004
  Oct9(5)417-21)

34
AntibioticsMoxifloxacin

• Randomized Controlled Trial on 320 patients
  (Italy) (Nista et al. Aliment Pharmacol Ther.
  2005 May 1521(10)1241-7)

35
Sequential therapy

• conventionnal therapy based on Rab-Am- Cla x 10
  days. (Randomized Controlled Trial on 96 patients
  De Francescu et al. Aliment Pharmacol Ther. 2004
  Feb 1519(4)407-14)
• the same results with the sequential regimen and
  half the dose of Cla (ER 94 with Cla 500 bid
  and 93 with Cla 250 bid)
• prospective, open-label study on 162 patients
  with non-ulcer dyspepsia and Helicobacter pylori
  infection (De Francescu et al. Aliment Pharmacol
  Ther. 2004 May 119(9)993-8)

36
First line therapy Duration

• Multi-center, Double-blind, randomized,
  parallel-group trial (USA). (Vakil et al. Aliment
  Pharmacol Ther. 2004 Jul 120(1)99-107)
• 803 patients with H. pylori infection with and
  without peptic ulcer disease in the United States
  

37
First line therapy Duration

• No difference between 7 and 10 days therapy
• Spanish randomized trial on 458 patients (Calvet
  et al. Am J Gastroenterol. 2005
  Aug100(8)1696-701)
• De Francisco et al. Dig Liver Dis. 2004
  May36(5)322-6)

38
First line therapy Duration

• Studies on Eso-omeprazole did not foud a
  difference between 7 and 10 days therapy
• (Gisbert et al. Am J Gastroenterol. 2005
  Sep100(9)1935-40)

39
First line therapy Duration

• Europe
• ? 7 days
• Conference de consensus HP. Gastroenterol Clin
  Biol 199923C95-104
• consensus report of Maastricht 2-2000

40
First line therapy Duration

• USA
• ? 10 days with PPI
• ? 14 days with RBC
• (Suerbaum et al. N Engl J Med 20023471175-86)

41
Second line therapy

• ? EF, why ?
• bad compliance
• or
• resistance ?
• ? Eradication of HP, is it indicated ?

42
Second line therapy

• Lower ER due to Metronidazole or Clarithromycin
  resistance
• do not associate Cla and Met in the first line
  therapy ? induction of double resistance
• (Peitz et al. Aliment Pharmacol Ther
  200216315-24)
• Cla Met induces more resistance than Cla Am
  (Lind et al. Gastroenterology 1999116248-53)
• Do not use quadritherapy in the first line
  therapy (Gisbert et al. Review article. Aliment
  Pharmacol Ther 2002161047-57)
• Quadri ? Tri ER 73
• Tri ? Quadri ER 92

43
Second line therapy

• Change the combination
• Am Cla ?? Met
• ER vaies from 50 to 80
• Gisbert et al. Eur J Gastrornterol Hepatol
  1999111049-54
• Nagahara et al. J Gastrornterol Hepatol
  200116613-8
• Gisbert et al. Review article. Aliment Pharmacol
  Ther 2002161047-57

44
Second line therapyBismuth Based Therapies

• 80 ER as a second line therapy
• Gasbarrini et al. Aliment Pharmacol Ther
  20001479-83

45
Second line therapy

• Prolong therapy duration and Culture ??
• A frensh prospective randomized study after
  first line EF

46
Second line therapy

• Change the PPI ?
• Controversial results
• Poor statistical methodology in most trials
• Cannot be recommended

47
Second line therapy Levofloxacin

• second line therapy  Cla resistant strains
• Open-label and randomised trial on 60 patients -
  Japan)
• Matsumoto et al. Dig Liver Dis. 2005 Jul 21

48
Second line therapy Rifabutine

• Used in both Metronidazole and Clarithromycin
  resistance
• Rifabutine-Am-Om for 7 days gave favorable
  results
• Miehlke et al. Gut 2002 51 (suppl 3) A212
• Perri et al. Am J Gastroenterol 2001 96 58-62

49
Second line therapyTetracycline furazolidone

• Randomized trial on 104 patients
• ER of 88 with La 30 mg bid Tetracycline 500
  qid Furazolidone 200 mg tid x 7 days
• ER of 26 with La 30 mg bid Am 1 g bid
  Azithromycin 500 qd (in the first 3 days)
• Frota et al. Arq Gastroenterol. 2005
  Apr-Jun42(2)111-5. Epub 2005 Aug 24

50
Second line therapy Rifampicin ???

• Rate of H. pylori infection is lower in patients
  taking clarithromycin and rifampicin for
  nontuberculous mycobacteriosis (33 )
• Second line therapy with clarithromycin and
  rifampicin --gt needs prospective trials
• Yokoyama et al. J Infect Chemother. 2005
  Aug11(4)173-6

51
Pediatric

• Trials on PPI-Am-Tinidazole ? ER 72 (Oderda et
  al. Helicobacter. 2004 Aug9(4)293-301)
• Trials on PPI-Am-Cla x 7 days ? 75 ER (Gottrand
  et al. J pediatr 2001139664-8)
• Trials on once daily dose did not yield
  acceptable results
• (Tindberg et al. Aliment Pharmacol Ther. 2004 Aug
  120(3)295-302)

52
Pediatric

• Eradicate only in the presence of gastritis or
  more
• Recommendations of
• Canadian association of gastroenterology (Hunt et
  al. Can J Gasroenterol 19981231-41)
• European pediatric concensus (J Pediatr
  Gastroenterol Nutr 2000 30 207-13)
• ? In case of clinical suspicion of gastritis or
  peptic ulcer disease ? gastroscopy with biopsy
  before any antibiotic therapy

53
Nutrition and Probiotics

• Lactobacillus casei
• OAC x 7 days vs OAC x 7 days supplemented with
  fermented milk (Actimel) containing L. casei
  DN-114 001
• x 14 days
• ? ER 57 vs 84 p 0.0045
• (L. casei) DN-114 001 strain (randomized,
  double-blind controlled studyon 86 children by
  Sykora et al. J Clin Gastroenterol. 2005
  Sep39(8)692-8)

54
Nutrition and Probiotics

• Trials with Lactobacillus and Bifidobacterium
  containing yogurt gave some favorable results
  (wang et al. Am J Clin Nutr. 2004
  Sep80(3)737-41)
• Other trials in the USA on broccoli and fermented
  milk did not show any benefic effect on HP status
  
• (Galan et al. Dig Dis Sci. 2004
  Aug49(7-8)1088-90)
• (Opekun et al. Methods Find Exp Clin Pharmacol.
  2005 Jun27(5)327-9)

55
Nutrition and Probiotics

• Most of the trials with probiotics suggested that
  probiotic supplementation reduces side-effects
  and permits better compliance
• (Myllyluoma et al Aliment Pharmacol Ther. 2005
  May 1521(10)1263-72)
• (Bergonzelli et al. Digestion. 200572(1)57-68.
  Epub 2005 Aug 18)
• (Tursi et al. Med Sci Monit. 2004
  Dec10(12)CR662-6)
• (Nista et al. Aliment Pharmacol Ther. 2004 Nov
  1520(10)1181-8)

56
Vaccination

• May decrease gastric cancer incidence in the USA
  from
• 4.5/100 000 ? 0.4/100 000
• (Runpow et coll. Vaccine 200120879-85)

57
Vaccination

• Cag A positive strains are more virulent and
  induce more protection
• urease based preparations are well tolerated and
  produce both humoral and cellular responses
• Efficacy is more pronounced in persons clear of
  HP
• needs for step II trial on non infected persons
  with more than 10 years FU
• Vaccine. 2004 Jun 222(17-18)2273-7
• GUT 200251634-40
• Vaccine 200119883-95
• Infet Immun 2002703529-38
• Infect immun 2001693581-90