The Management of Helicobacter Pylori

Dr. Tan Huck Joo
Consultant Gastroenterologist, UKM

Helicobacter pylori infects more than half of the population of the world. It has been associated with peptic ulcer disease, mucosal associated lymphoid tissue (MALT) lymphoma and gastric cancers. Eradicating Helicobacter pylori cures most ulcer disease and MALT lymphoma and prevents recurrence of peptic ulcer and its complications¹. Eradicating Helicobacter is more effective than maintenance anti-secretory therapy preventing ulcer recurrence². Although Helicobacter pylori eradication may prevent gastric cancer in some patients, screening and testing the general population is still controversial and not indicated.

Who to treat
Since its discovery in the early 1980's³, the treatment of Helicobacter pylori has come a long way. Given the different treatment indications and the demographic and socioeconomic diversities of the patient population being treated, the management of Helicobacter pylori varies from one region to another. Working parties from the US^4-6, Canada^7-8, Europe⁹ and Asia Pacific¹⁰ regions have developed guidelines to help physicians from the respective regions to manage Helicobacter pylori infection. The guidelines were generally based on published evidence and / or expert opinions. Cost and incidence of gastric cancer also guided recommendations.

Helicobacter pylori eradication is recommended in all the guidelines for peptic ulcer disease and MALT lymphoma. In addition, treatment is also recommended for severe gastritis, non ulcer dyspepsia, family history of gastric cancer, patients on long term proton pump inhibitors (PPI), patients taking non steroidal anti-inflammatory drugs (NSAID) or if the patient wishes, in the Maastricht Consensus. The Canadian guideline is similar to the Maastricht Consensus with the exception of gastroesophageal reflux disease (GERD) on long term PPI, non-ulcer dyspepsia, NSAID alone and asymptomatic patients. The Asia Pacific guidelines on the other hand included dyspeptic patienls on NSAID.

As a general rule, testing should only be done if treatment is contemplated. Once tested positive, treatment should be initiated and the most effective therapy should be used as first line therapy.

How to treat
Helicobacter pylori is sensitive to most common antibiotics. The ideal treatment must be effective, simple and well tolerated with few side effects. The treatment of Helicobacter pylori has undergone major changes with the development of newer drugs over the years. Bismuth compound was the main drug used from 1984 to 1990, often as monotherapy or in combination with antibiotics, either metronidazole, amoxydilin or tetracydine for 2 weeks. However failed eradication therapy was increasing mainly due to the increase in bacteria resistant to antimicrobials. The arrival of PPI in the early 1990's has revolutionalised the Helicobacter pylori treatment. Bazzoli's regimen¹¹ using PPI low dose triple therapy in 1993 has become the cornerstone for the new era of Helicobacter pylori eradication. This was later on confirmed in large multicentre trials, the MACH 1¹² and MACH 2¹³. The commonest regimen of choice in all the guidelines was PPI or Ranitidine bismuth citrate (RBC) plus clarithromycin with either amoxycillin or metronidazole taken for 7 days (Europe, Canada and Asia Pacific) or 14 days (USA). Less effective acid suppressive therapy using H2 antagonist as triple therapy is not as effective¹⁴ and should not be used.

First line therapy
PPI-basedl2 or RBC-based triple therapies have consistently achieved high eradication rate of more than 90% in trial setting compared to dual therapies (25% to 72%). This has been quite consistent in different parts of the world¹⁵. There is also no significant difference between the different types of PPI¹⁶ in Helicobacter pylori eradication therapy. As expected, the eradication rate in clinical practice (72% and 73% for OAC and OCM respectively)¹⁷ is lower than the rates achieved with similar regimens in the clinical trial setting. In an attempt to find the optimal duration of RBC-hased triple therapies, 7-day therapy was found to be the most optimal. Four-day treatment only achieved 60% eradication rate whereas 10-day therapy did not have any therapeutic gain compared to 7-day therapy¹⁸. Shorter course (5-day) of therapy has also been reported to be well tolerated and effective^19-21. However more trials are required.

Treatment failure
PPI or RBC based triple therapies achieve eradication rate of 80 to 90%. This means that 10-20% of the patients will still have treatment failure. The commonest reasons for treatment failure are bacterial resistant to antimicrobials, patient non-compliance and possibly non-ulcer dyspepsia versus peptic ulcer patients. A meta-analysis²² of 20 nationwide trials (USA) of Helicobacter pylori eradication revealed that predictors for clarithromycin resistance were older age group, female gender, inactive ulcer disease and year of study whereas female sex, Asian ethnicity and earlier year of enrolment were significantly associated with metronidazole resistance. Osato²³ also demonstrated that both metronidazole and clarithromycin resistance were more common in women than men. Antibiotic resistance also increases gradually up to the age of 70 years, then declines significantly. Pretreatment with omeprazole does not significantly reduce the efficacy of eradication therapy in peptic ulcer disease patients²⁴.

Author/year	Country	Metronidazole	Clarithromycin	Amoxycilin
Mendonca 2000	Brazil	42%	7%	29%
Osato 1999	US	37.4%	6.1%
Boyanova 2000	Bulgaria	28.6%	9.7%
Debets-Ossenkopp 99	Netherlands	21.2%	1.7%	0%
Lopez-Borea 1995	Spain	21.6%	4.4%
Ellenrieder 1999	Germany	22.9%	4.9%
Pilotto 2000	Italy	14.9%	1.8%	0%
Wang 2000	Hong Kong	49.4%	10.8%
Huang 2000	Taiwan	36%	6%	0%
Kim 2001	Korea	40.6%	5.9%	0%
Wongkusoltham 2001	Thailand	51.9%
Salasawati 2001	Malaysia	39.2%
Table 1 : Antimicrobial resistance in different countires

Antimicrobial resistance
Several antimicrobial resistance have been described (Table 1). The commonest is metronidazole followed by clarithromycin. Amoxycillin and tetracycline resistance is still quite rare. Metronidazole and clarithromycin resistance can either be primary (resistance to antibiotic that is there prior to treatment) or acquired (resistance which develops following therapy in strains which are originally sensitive) resistance. For metronidazole resistance, E-test or agar dilution method is the commonest test used. Minimal inhibitory concentration (MIC) of >8ug/ml or 16 ug/ml is considered metronidazole resistance whereas MIC>2 ug/ml is considered clarithromycin resistance.

Metronidazole or clarithromycin resistance is on the rise worldwide. For instance, metronidazole resistance had risen from 22% in 1991 to 73.2% in 1995 in Hong Kong²⁵. The corresponding figure for Spain²⁶ was 9% to 21.6% for the same period. Similarly, clarithromycin resistance which was rare in the early 1990's (0%) had gone up to 4.4% in 1995 in Spain. Generally metronidazole resistance ranges from 10% to 50% in the western world and 40% to 80% in the Asia Pacific region whereas clarithromycin resistance ranges from 0% to 20%. Resistance to antimicrobial is an important issue because of its clinical impact on the efficacy of eradication therapy. The eradication rate for metronidazole resistant strains using PPI-based triple therapy in combination with metronidazole and clarithromycin (OCM) was 80% compared with 45% for orneprazole, amoxycillin and metronidazole (OAM) whereas for sensitive organism, the eradication rate was 94% and 79% respectively²⁷. Therefore OCM is a well tolerated, effective treatment for Helicobacter pylori eradication even with metronidazole resistant strain. For RBC-based triple therapy, metronidazole resistance can he overcome by using a combination of metronidazole and clarithromycin where eradication rates of 98% and 95% were reported for metronidazole sensitive and resistant strains respectively. Again a combination using amoxycillin and metronidazole with RBC showed inferior results where eradication rates of 87% and 22% were reported for sensitive and resistant strains²⁸ respectively. A head-to-head comparison between RBC-based and PPI-based triple therapy using the same antibiotics (RBC-CM vs OCM) showed that RBC is more superior than PPI or bismuth based eradication therapy especially in resistant strains (RBC-CM 94%, OCM 57%, BAM 38%)²⁹.

On the other hand, the prevalence of clarithromycin resistance, which is thought to have more clinical significance than metronidazole resistance, is still relatively low. However, the presence of clarithromycin resistant strains reduces the eradication rate significantly (0-40%)^30-32. Fortunately, dual antimicrobial resistance is still quite rare but the prevalence of as high as 7.2% has been reported in Hong Kong. This certainly will have a major impact on the treatment of Helicobacter pylori. Therefore, although PPI or RBC based triple therapy with clarithromycin and metronidazole is an effective option, they may theoretically lead to the development of dual resistance. This combination should be avoided if possible.

The most important predictor to overcome primary and secondary resistance is to use the most effective regimen with a high cure rate of infection. Secondary resistance is very high in treatment failure (acquired metronidazole resistance 40%,clarithromycin resistance 35-65%)^33-35 especially in those treated with dual therapy (90.9%)33. Therefore dual therapy should not be used because of its ineffectiveness and the high risk of secondary resistance. There are also some data to suggest that RBC is better than PPI in preventing secondary resistance. Megraud³⁶ et al demonstrated that only 3% (1/39) of their patients who failed RBC plus clarithromycin (RBC+C) developed resistance to clarithromycin compared to 18% (8/44) in the omeprazole plus clarithrornycin group (p<0.05). Osato³⁷ et al reported similar findings where 66% (19/29) in the RBC+C group versus 84% (41/49) of O+C group developed clarithromycin resistance (p<0.05).

Patient compliance
Patient compliance is another important factor for treatment success. No matter how good the treatment is, if the patient does not take the medication then it will not work. Most patients are non-compliant because of forgetfulness, laziness or side effects. It is very important to explain to the patients the impact of failed eradication therapy. It is also important to warn them of possible side effects. Fortunately most first line triple therapies (taken twice daily for 7 days) are easy to remember and take. Although patient compliant has a great impact on the outcome of eradication therapy, this has not been a major issue in most clinical trials. Attempts have been made to shorten the duration to improve compliance^20,21. This might be possible but more data are needed before it can be recommended as a routine clinical practice.

Peptic ulcer disease versus non-ulcer dyspepsia
There is some evidence to suggest that the failure rate of eradication is higher in the non-ulcer dyspepsia (NUD) group compared to the duodenal ulcer (DU) group. Broutet38 et al showed that failed eradication rate for NUD and DU was 33.7% and 21.9% respectively in a large number of patients. Similar finding was also reported in a meta-analysis by Huang and Hunt39. The reason for this is not known.

Second line / rescue / salvage therapies
Papers published on this subject are difficult to analyze. Quadruple therapy (PPI, bismuth, tetracycline, metronidazole) for 1 week is the recommended second line therapy in some guidelines. Unfortunately, this often is not the optimal treatment because it depends very much on the primary regimen prescribed, 7-day quadruple therapy was shown to be useful after failed dual therapy⁴⁰and triple therapy containing amoxycillin and clarithromycin⁴¹ but results were less good if the primary regimen contains metronidarole⁴². Therefore the choice of the primary regimen and the assumed secondary resistance dictate the choice of second line therapy. There are some data suggesting that longer duration of treatment achieved excellent results even in cases of secondary metronidazole resistance. It is important to use a higher dosage of metronidazole in cases of failure. The eradication rate for quadruple therapy was consistently high in those who had failed PPI-AC as first line^43,44. If a PPI-based triple therapy is used as a second line therapy, it should then be given for 14 days. Quadruple therapy for 7 days on the other hand achieve equivalent efficacy to the 14 days triple therapy, but was significantly better than 1-week PPI-triple therapy¹⁷.

Other alternatives
Other drug regimen that has been tried as a rescue therapy included PPI, amoxycillin and rifabutin. Perri et al demonstrated that this combination in fact was far more superior than the quadruple therapy with fewer side effects⁴⁵. Furazolidone was also tried in a small group of patients and was proposed as a salvage therapy⁴⁶. Clearly more data are needed.

Recommendation for therapy
The treatment of choice as first line therapy depends very much on the local prevalence of antimicrobial resistance. In areas with high metronidazole resistance, PPI/RBC-AC is a good choice and quadruple therapy can be reserved as a second-line treatment. In areas with high clarithromycin resistance, however, PPI/RBC-AM can be used instead provided that the metronidazole resistance is not a major problem as this combination is not effective in overcoming metronidazole resistant strains. Quadruple therapy should be used as a first line therapy in these cases. Triple therapy PPI/RBC-AC can then be used as second line therapy. Patients who failed second line therapy should undergo sensitivity testing and the treatment option then depends on the antibiogram⁴⁷.

Conclusion
Helicobacter pylori is an important discovery as it has revolutionalized our understanding and management of peptic ulcer disease. Many guidelines have been published and PPI/RBC-based triple therapy is the recommended therapy of choice. It is the responsibility of all the clinicians treating this particular organism to choose the best sensible treatment option available to eradicate the organism and its complication. It is also important for us to ensure that we avoid secondary bacterial resistance to anti-microbials. Hopefully more drugs will be available to tackle the rising problem of eradication failure.

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