Helicobacter pylori in Developing Countries

World Gastroenterology Organisation Global Guideline Helicobacter pylori in Developing Countries ... not all the management methods for...

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World Gastroenterology Organisation Global Guideline Helicobacter pylori in Developing Countries

INTRODUCTION Helicobacter pylori is found in half the population of the world. Its prevalence is highly variable in relation to geography, ethnicity, age, and socioeconomic factors— higher in developing countries and lower in the developed world. In general, however, there has been a decreasing trend in the prevalence of H. pylori in many parts of the world in recent years. Direct epidemiologic comparisons of peptic ulcer disease (PUD) between developing and developed countries are complex, as peptic ulcers may be asymptomatic and the availability and accessibility of the tests required for diagnosis vary widely. In developing countries, H. pylori infection is a public health issue. The high prevalence of the infection means that public health interventions may be required. Therapeutic vaccination is probably the only strategy that would make a decisive difference in the prevalence and incidence of H. pylori throughout the world. The short-term approach, however—provided that resources allow for this—would be a test-and-treat strategy for those who are at risk for PUD or gastric cancer and for those with troublesome dyspepsia. Note by Prof. Barry Marshall, Nobel Laureate, Helicobacter Research Laboratory, University of Western Australia, Perth, Australia “Luckily, not all the management methods for H. pylori are expensive, and logical analysis of the disease characteristics in each country can lead to an optimal treatment plan. Initially, not all patients with H. pylori can be treated, because resources are limited. However, eradication of the ubiquitous ‘ulcer bug’ is the first step in freeing patients with chronic dyspepsia and/or ulcer disease from an expensive lifetime of chronic medication use. Noninvasive ‘test-and-treat’ strategies have to be balanced with clinical factors and an estimate of the possible cancer risk in each patient.

Supported by none. Conflict of Interest: None. Review team: R.H. Hunt, Chair (Canada), S.D. Xiao (China), F. Megraud (France), R. Leon-Barua (Peru), F. Bazzoli (Italy), S. van der Merwe (South Africa), L.G. Vaz Coelho (Brazil), M. Fock (Singapore), S. Fedail (Sudan), H. Cohen (Uruguay), P. Malfertheiner (Germany), N. Vakil (USA), S. Hamid (Pakistan), K.L. Goh (Malaysia), B.C.Y. Wong (Hong Kong), J. Krabshuis (France), and A. Le Mair (The Netherlands). Copyright r 2011 by Lippincott Williams & Wilkins

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This paper strikes a practical and useful balance. As you develop expertise in your own area, I am sure that you can even improve on the strategies listed here.”

Epidemiology: Global Aspects Globally, different strains of H. pylori seem to be associated with differences in virulence, and the resulting interplay with host and environmental factors leads to subsequent differences in the expression of disease. Age, ethnicity, sex, geography, and socioeconomic status are all factors that influence the incidence and prevalence of H. pylori infection. The overall prevalence is higher in developing countries and lower in developed countries and within areas of different countries. There may be similarly wide variations in the prevalence between more affluent urban and rural populations. The principal reasons for these variations involve socioeconomic differences between populations. Transmission of H. pylori is largely by the oral-oral or fecal-oral routes. Lack of proper sanitation, safe drinking water, and basic hygiene, and poor diets and overcrowding, all play a role in determining the overall prevalence of infection.  The global prevalence of H. pylori infection is >50%.  The prevalence may vary significantly within and between countries.  In general, H. pylori seropositivity rates increase progressively with age, reflecting a cohort phenomenon.  In developing countries, H. pylori infection is markedly more prevalent at younger ages than in developed countries (Table 1).

DIAGNOSIS OF H. pylori INFECTION Diagnostic tests for H. pylori infection include endoscopic and nonendoscopic methods. The techniques used may be direct (culture, microscopic demonstration of the organism) or indirect (using urease, stool antigen, or an antibody response as a marker of disease). The choice of test depends, to a large extent, on availability and cost, and includes a distinction between tests used to establish a diagnosis of the infection and those used to confirm its eradication. Other important factors are clinical situation, population prevalence of infection, pretest probability of infection, differences in test performance, and factors that may influence the test results, such as the use of antisecretory treatment and antibiotics (Tables 2 and 3). Serological testing is less accurate than breath testing and stool antigen testing, particularly in areas of low H. pylori prevalence. Its lower positive predictive value has led to concerns in western countries that antibiotics are www.jcge.com |

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Africa Ethiopia Ethiopia Ethiopia Nigeria Nigeria Central America Guatemala Guatemala Mexico North America Canada Canada USA and Canada South America Bolivia Brazil Brazil Brazil Chile Chile Asia Bangladesh Bangladesh Bangladesh Bangladesh Hong Kong India India India India, south Japan, 3 areas Japan, western Siberia Siberia Siberia South Korea South Korea Sri Lanka Sri Lanka Taiwan Taiwan Taiwan Australasia Australia Europe Eastern Western Albania Bulgaria Czech Republic Estonia Germany Iceland Netherlands Serbia Sweden Switzerland Switzerland Middle East Egypt Egypt Libya

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TABLE 1. (continued)

TABLE 1. Helicobacter pylori Infection Globally

Country



Age Groups (y)

Prevalence (%)

2-4 6 Adults 5-9 Adults Adults

48 80 >95 82 91 70-90

5-10 Adults 5-9 Adults

51 65 43 70-90

5-18 50-80 Adults

7.1 23.1 30

5 6-8 10-19 Adults 3-9 Adults Adults

54 30 78 82 36 72 70-90

0-2 0-4 8-9 Adults 6-19 0-4 10-19 Adults 30-79 20-70+ Adults 5 15-20 Adults 16 Z16 6-19 Adults 9-12 13-15 Z25 Adults

50-60 58 82 >90 13.1 22 87 88 80.0 55.4 70.1 30 63 85 56.0 40.6 67 72 11.0 12.3 45.1 50-80

1-59 Adults

15.4 20

Adults Adults 16-64 1-17 5-100 25-50 50-74 25-50 2-4 7-18 25-50 18-85 18-85

70 30-50 70.7 61.7 42.1 69 48.8 36 1.2 36.4 11 26.6 11.9

3 Adults 1-9

50 90 50

Country

Age Groups (y)

Prevalence (%)

10-19 Adults 5-9 Adults 6-17 Adults

84 94 40 80 64 80

Libya Libya Saudi Arabia Saudi Arabia Turkey Turkey

possibly being administered unnecessarily after serology testing. However, this traditional view is not universally applicable in countries with a high H. pylori prevalence. In a low-prevalence area, serology works less well, so that a negative test has more value than a positive test. In a highprevalence area, a positive serology test can reasonably be accepted as positive. A rigorous process of identification and exclusion of H. pylori infection is required.  In developed countries, – The use of a test-and-treat strategy for younger patients presenting with dyspepsia is declining. – The immediate use of an antisecretory drug (proton pump inhibitor, PPI) is usually preferred as a first-line treatment when the H. pylori prevalence is <20%. – For those aged 50 years and older, endoscopy to exclude an upper gastrointestinal malignancy and testing for H. pylori infection if no malignancy is found remains a logical approach. – Testing for H. pylori infection should be carried out in younger patients in countries with a high risk of gastric cancer.  In developing countries in which the rates of ulcer or gastric cancer are high, an empirical test-and-treat approach or initial endoscopy is a more appropriate initial approach than starting treatment with a PPI.

Good Practice Point It should be ensured that patients undergoing a breath test, stool antigen test, or endoscopy are free from medication with PPIs or histamine2-receptor antagonists for a minimum of 2 weeks and antibiotics for 4 weeks before testing. TABLE 2. Tests for Helicobacter pylori Infection Tests with endoscopy Rapid urease test Histology Culture* Fluorescence in situ hybridization Molecular approach: polymerase chain reaction Tests without endoscopy Stool antigen testw Finger-stick serology test Whole-blood serologyz 13 C urea breath test 14 C urea breath test *Culture may not be practical in all countries; treatment choices are often based on what is known about resistance patterns. wDespite being a good test, stool antigen testing may be underused, due to its high costs, in Pakistan and some other countries/regions. zIn high-prevalence areas, the definition of the serological cutoff value distinguishing between active infection and background infection may be problematic.

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TABLE 3. Comparison of Diagnostic Tests for Helicobacter pylori Infection

Sensitivity (%)

Specificity (%)

Positive Predictive Value (%)

Rapid urease test

>98

99

99

Histology

>95

>95

85-92

79-83

64

95

96

88

95

94

84

Test

Culture

PCR ELISA serology

13

C/14C urea breath test

Stool antigen

Finger-stick serology test

Comments Rapid and cheap Posttreatment sensitivity reduced Detection improved by use of special stains—for example, the Warthin-Starry silver stain, or the cheaper hematoxylin-eosin stain or Giemsa staining protocol Highly specific, poor sensitivity if adequate transport media are not available Experience/expertise required Expensive, often not available Sensitive and specific Not standardized Considered experimental Less accurate and does not identify active infection Reliable predictor of infection in (high-prevalence) developing countries Not recommended after therapy Cheap and readily available Recommended for diagnosis of Hp before treatment Preferred test for confirming eradication Not to be performed within 2 weeks of PPI therapy or within 4 weeks of antibiotic therapy Variable availability Not often used despite its high sensitivity and specificity before and after treatment Should have a more prominent place, as it is inexpensive and noninvasive Very poor and cannot be equated with ELISA serology

ELISA indicates enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; PPI, proton-pump inhibitor.

MANAGEMENT OF H. pylori INFECTION The aim of H. pylori eradication is to cure PUD and reduce the lifetime risk of gastric cancer. Although the burden of gastric cancer is increasing—mostly in developing countries, due to increasing longevity—eradication of H. pylori infection has the potential to reduce the risk of gastric cancer. The stage in the natural history of the infection at which eradication of H. pylori prevents gastric cancer is uncertain. There may be a point of no return, before which eradication is successful in preventing later development of gastric cancer. The appearance of mucosal precursor lesions may prove to be this point of no return. Once these precursor lesions have appeared, H. pylori eradication may no longer be effective in preventing gastric cancer. As most people are infected soon after birth, these precursor lesions may be occurring quite early in life, and better information

TABLE 4. Indications for Treatment of Infection in Helicobacter pylori-positive Patients 1. Past or present duodenal and/or gastric ulcer, with or without complications 2. Following resection of gastric cancer 3. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma 4. Atrophic gastritis 5. Dyspepsia 6. Patients with first-degree relatives with gastric cancer 7. Patient’s wishes

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in different parts of the world is needed to time interventions optimally (Table 4). H. pylori eradication treatment is supported by numerous consensus groups around the world and is generally safe and well tolerated. The standard treatment is based on multidrug regimens.  A vaccine is not currently available, and as the exact source of H. pylori infection is not yet known, it is difficult to make recommendations for ways of avoiding the infection.  In general, however, it is always wise to observe good public health measures, to wash hands thoroughly, to eat food that has been properly prepared, and to drink water from a safe, clean source.  Pediatric patients who require extensive diagnostic workup for abdominal symptoms should be referred for evaluation by a specialist.  H. pylori eradication does not cause gastroesophageal reflux disease.

Choosing an Eradication Regimen The following factors need to be taken into account when choosing a particular treatment approach: they may vary in different continents, countries, and regions. The management of H. pylori infection in high-prevalence areas should be similar to that in low-prevalence areas (Table 5).

Compliance Commitment on the part of the patient is required for 3 or 4 different drugs to be taken in combination 2 to 4 www.jcge.com |

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TABLE 5. Factors Involved in Choosing Treatment Regimens Prevalence of Helicobacter pylori infection Prevalence of gastric cancer Resistance to antibiotics Cost level and available budget Availability of bismuth Availability of endoscopy, H. pylori tests Ethnicity Drug allergies and tolerance Previous treatments, outcome Effectiveness of local treatment Ease of administration Adverse effects Recommended dosages, treatment duration



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– Cost considerations and compliance issues may still favor 7-day therapy. – Some groups suggest treatment for 10 days.  Quadruple therapy. PPI+bismuth+2 antibiotics: amoxicillin+clarithromycin, or metronidazole+tetracycline. – May be cheaper than triple therapy. – More difficult to take than triple therapy. – Equivalent or superior eradication rates.

Antibiotic Resistance Antibiotic resistance is a key factor in the failure of eradication therapy and recurrence of H. pylori infection. Antibiotic resistance rates are increasing throughout the world. They vary geographically and are higher in developing countries (Table 6).

times a day for up to 14 days, with a likelihood of adverse effects such as malaise, nausea, and diarrhea.

Good Practice Point It should always be emphasized to the patient that successful eradication depends on full compliance with the treatment. Time should be taken to counsel the patient, explaining the procedures involved in taking complicated drug therapies such as quadruple therapy and describing the side effects—this will improve compliance and outcome.

Good Practice Point If treatment fails, antibiotic sensitivity testing may be considered, if available, to avoid choosing H. pyloriresistant antibiotics.

Rescue Therapy There is considerable variation between consensus groups with regard to the optimal “rescue” therapies (Table 7).

First-line Treatment Regimens  Triple-therapy treatment regimens. PPI+2 antibiotics: amoxicillin and clarithromycin, or metronidazole and clarithromycin. – Used and accepted worldwide. – Standard PPI-based therapy fails in up to 30% of patients. Eradication rates have fallen to 70% to 85% over the last few years, in part because of increasing clarithromycin resistance. – A longer treatment duration may increase eradication rates, but remains controversial: studies suggest an increase to 14 days instead of 7 days.

CASCADE INFORMATION Cascade for Diagnosing H. pylori: Options for Developing Countries (Table 8) Note 1. The gold standard—endoscopy with rapid urease testing—is not readily available in all parts of the world. Cost-effectiveness considerations play a major role in all resource settings. In low-resource communities, considerations of precision and sensitivity may sometimes be traded against costs and the availability of resources.

TABLE 6. Antibiotic Resistance of Helicobacter pylori

Country (y) Africa Senegal (2009) Nigeria (1999) Asia India (2003) India (2005) South-East Asia (2006) Taiwan (2009) China (2007) Thailand (2009) Middle East Iran (2007) Egypt (2004) Saudi Arabia (2002) Kuwait (2006) South America Argentina (2006) Brazil (2002) Colombia (2009)

No. Tested

Amoxicillin (%)

Metronidazole (%)

Clarithromycin (%)

Quinolones (%)

40 50

0 0

90 55

13

0 13

259 67 72

33 0 19

78 85 100

45 0 28

3

227 340 221

0 3 7

27 76 39

11 28 3

9

101 48 223

21 2 1

73 100 80

9 4 4

5 2

96

0

70

0

0

2

53 82

24 9 4

0

242 202 106

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Furazolidone (%)

0

Tetracycline (%)

4 7

7

3 9

5 0.5

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TABLE 7. Rescue Therapies

Rescue Options After Initial Treatment Fails Repeat treatment with a different combination of medications PPI b.i.d.+tetracycline (500 mg) t.i.d.+bismuth q.i.d.+metronidazole (500 mg) t.i.d.10 d PPI+amoxicillin (1 g) b.i.d.+levofloxacin (500 mg) b.i.d. 10 d

Comments The choice should take account of the local antibiotic resistance of Helicobacter pylori Cheap, high pill burden, many side effects Eradication rate 87%

b.i.d. indicates bis in die (twice a day); PPI, proton-pump inhibitor; q.i.d., quater in die (4 times a day); t.i.d., ter in die (three times a day).

Note 2. In some regions where H. pylori prevalence is very high, diagnostic tests for the infection are not costeffective. The decision to treat must then assume the presence of H. pylori infection.

Good Practice Point Treat everyone who tests positive—do not test if not intending to treat.

Ten Cascade Notes for Managing H. pylori Note 1. In high-prevalence areas with limited resources, a trial of H. pylori eradication may be used in an appropriate clinical setting. On account of the high cost of medicines, alternatives to PPI triple-therapy combinations, using generic drugs such as furazolidone, may have a place. Generic PPIs are becoming increasingly available around the world. Note 2. Antibiotic resistance is high in developing countries and is increasing in developed countries. The antibiotics used must be carefully considered, particularly when there is known antibiotic resistance. Note 3. There is geographic variability in the efficacy of PPIs in the treatment of PUD because of differences in body weight, CYP2C19 genetic polymorphisms, and drug TABLE 8. Resource Levels and Diagnostic Options

Resource Level* 1 2 3 4 5 6 7

Diagnostic Options Endoscopy with RUT, histology (culture is not practical in most countries) 13 C UBT 14 C UBT Stool antigen testing Whole-blood serology (does not distinguish between past and present infection) Finger-stick serology test (cheaper option in highprevalence areas; new-generation tests are more accurate)w Do no further testing and assume the patient is infected in areas with a very high prevalence and low resources

*Resource levels 1 to 7 represent a scale ranging from all resources (level 1) to no resources (level 7). wCaution: The literature suggests that the accuracy of finger-stick serology is too low for it to be recommended and that new tests are better. RUT indicates rapid urease test; UBT, urea breath test.

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response. PPIs relieve pain and heal peptic ulcers more rapidly than H2-receptor antagonists. Although H2-receptor antagonists do inhibit acid secretion, PPIs are preferable because of their superior efficacy and lack of tachyphylaxis. However, it is still necessary to use them in a twice-daily regimen. Note 4. Bismuth is a key consideration, as it is not available in all countries. The Maastricht III Consensus Report concluded that the eradication rates and confidence intervals for bismuth-based quadruple therapy and standard triple therapy are broadly similar, and bismuth-based therapy is considerably cheaper than several other choices.  It has been assumed that bismuth subsalicylate and colloidal bismuth subcitrate are equivalent.  Poorly absorbed, <1%.  Mechanism of action unknown.  Affordable cost.  In the 1970s, bismuth salts were associated with neurotoxicity (with high doses used for long periods).  Bismuth therapies have therefore been banned in some countries, such as France and Japan. Note 5. Furazolidone has a place in the treatment of H. pylori in developing countries with a high H. pylori prevalence and limited resources.  It has the lowest cost among anti-H. pylori drugs.  It is effective against H. pylori strains with low resistance rates.  Its mechanism of action is unknown.  It has been recommended as an alternative option by the Latin American (2000), second Brazilian (2005), World Gastroenterology Organization (2006), and third Chinese (2008) consensus conferences.  It has possible genotoxic and carcinogenic effects in animals.  It is no longer available in the United States or in the European Union. Note 6. Tetracycline is also an effective drug against H. pylori and can be recommended in eradication regimens. Tetracycline is not only effective against H. pylori, but also has low resistance and is cheap. Note 7. Generic drugs are used in many countries, and a lack of adequate quality control may explain treatment failures. TABLE 9. Gold Standard Treatment Options

Publisher American Gastroenterological Association (2005) Second Asia–Pacific Consensus Conference (2009) Maastricht III (2009) American College of Gastroenterology (2007) Third Chinese National Consensus Report (2008) National Institute for Health and Clinical Excellence (NICE), UK (2004) Scottish Intercollegiate Guidelines Network (SIGN), UK (2003)

Web Address http://www.gastrojournal.org/ article/S0016-5085(05)018184/fulltext http://www.apage.org http://gut.bmj.com/content/56/ 6/772 http://www.acg.gi.org/ physicians/guidelines/ ManagementofHpylori.pdf http://www3.interscience.wiley. com/journal/120835370/ abstract http://guidance.nice.org.uk/ CG17 http://www.sign.ac.uk/pdf/ 2009dyspepsiareport.pdf

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TABLE 10. Treatment Options in Developing Countries

Notes (A) First-line therapies PPI+amoxicillin+clarithromycin, all b.i.d. for 7 d

Used and accepted throughout the world Eradication rates have fallen to 70% to 85% over the last few years, in part due to increasing resistance to clarithromycin Cost considerations and compliance issues may favor 7-d therapy Some groups suggest treatment for 10 or 14 d Other inexpensive macrolides, such as azithromycin, are available over the counter in developing countries, and macrolide cross-resistance affects eradication rates In case of a clarithromycin resistance rate of >20%: Quadruple May be cheaper than triple therapy therapy: PPI b.i.d.+bismuth+tetracycline+metronidazole all More difficult to take than triple therapy. A single triple capsule q.i.d. for 7-10 d has been shown to facilitate its use Equivalent eradication rates in comparison with standard triple therapy In vitro metronidazole resistance may be overcome by prolonging therapy or using high doses of metronidazole If there is no known clarithromycin resistance or clarithromycin resistance is not likely PPI+amoxicillin+clarithromycin for 7 d Quadruple therapy: PPI+bismuth+tetracycline+metronidazole for 7-10 d If bismuth not available: concomitant therapy: PPI+clarithromycin+metronidazole+amoxicillin for 14 d Furazolidone-containing regimens: PPI+furazolidone+antibiotic is slightly less effective than the standard triple regimens Furazolidone can replace amoxicillin in standard triple therapy Sequential regimen: 10-d therapy with PPI+amoxicillin for 5 d followed by PPI+clarithromycin and a nitroimidazole (tinidazole) for 5 d (B) Second-line therapies, after failure of clarithromycin-containing regimens PPI+bismuth+tetracycline+metronidazole for 10-14 d PPI+amoxicillin+levofloxacin for 10 d PPI+furazolidone+tetracycline+bismuth for 10 d PPI+furazolidone+levofloxacin for 10 d PPI+amoxicillin+clarithromycin for 7 d PPI+amoxicillin+levofloxacin for 10 d PPI+furazolidone+levofloxacin for 10 d (C) Third-line therapies, after failure of clarithromycin-containing regimens and quadruple therapy PPI+amoxicillin+levofloxacin for 10 d PPI+amoxicillin+rifabutin for 10 d PPI+furazolidone+levofloxacin for 7-10 d B.i.d. indicates bis in die (twice a day); PPI, proton-pump inhibitor; q.i.d., quater in die (four times a day).

Note 8. In Brazil, patients with a history of allergy to penicillin receive PPI+clarithromycin (500 mg) and furazolidone (200 mg) twice daily for 7 days. Note 9. Reports from Asia suggest that 1 week of triple PPI therapy with clarithromycin and amoxicillin is still a useful form of treatment. Metronidazole resistance in Asia is close to 80% (in vitro). Note 10. Prescribers should be aware of drug resistance patterns in their own area (particularly with regard to clarithromycin) before deciding on a particular regimen.

Gold Standard Treatment Options Further information on gold standard treatment options is available in the documents listed in Table 9.

Treatment Options in Developing Countries (Table 10) Lower-cost Options for Limited-resource Settings (Table 11)

TABLE 11. Cost-reducing Alternative Helicobacter pylori Eradication Regimens

Alternative Regimens 7 or 10 d duration instead of 14 d for standard triple therapy Quadruple instead of triple therapy (if bismuth is available) PPI+furazolidone+tetracycline (low-cost option) Rabeprazole+levofloxacin+furazolidone Furazolidone+amoxicillin+omeprazole+bismuth citrate Furazolidone+amoxicillin+omeprazole Furazolidone+lansoprazole+clarithromycin PPI+rifabutin+amoxicillin

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Recommended by Maastricht III Maastricht III Brazil and Latin America Consensus Coelho et al, Aliment Pharmacol Ther 2005;21:783–787 Darian (Iran) Massart (Iran) Coelho et al, Aliment Pharmacol Ther 2003;17:131–136 Xia et al, Expert Opin Pharmacother 2002;3:1301–1311 Second Asia–Pacific Consensus Guidelines for Helicobacter pylori Infection

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