Sources of variation of Helicobacter pylori treatment success in adults worldwide: a meta-analysis

Lori A Fischbacha, Karen J Goodmanb, Mark Feldmanc and Corinne Aragakia

a School of Public Health at Dallas, University of Texas—Houston, Health Science Center.
b School of Public Health, University of Texas—Houston, Health Science Center.
c Presbyterian Hospital of Dallas and The University of Texas Southwestern Medical Center at Dallas.

Lori Ann Fischbach, MPH Program at UT Southwestern, 5323 Harry Hines Blvd, V8.112, Dallas, TX 75390–9128, USA. E-mail: Lori.Fischbach{at}UTSouthwestern.edu

Abstract

Background A vast number of Helicobacter pylori treatment trials have been conducted. Regimens may vary in efficacy in different patient populations.

Methods We identified sources of treatment effect variation from 618 treatment groups using weighted cross-classified multi-level meta-regression models. Summary effect estimates were calculated within groups that lacked identified heterogeneity.

Results Overall, treatment was less successful with shorter treatment duration and dual drug (versus triple or quadruple drug) therapies. For nitroimidazole-based regimens, treatment was less successful in populations with frequent childhood H. pylori infection or metronidazole resistance and more successful in northeastern Asia. Non-nitroimidazole treatments of longer duration and those from less recent reports were most successful. Some one-week regimens—(nitroimidazole/ tetracycline/bismuth, ranitidine bismuth citrate/amoxicillin/clarithromycin, and clarithromycin/amoxicillin/proton pump inhibitor) were highly successful in northeastern Asia regardless of metronidazole resistance. The most successful regimen in populations with both a high prevalence of metrondiazole resistance and frequent infection in children (metronidazole/furazolidone/amoxicillin) eliminated fewer than 70% of infections.

Conclusions More effective treatments are needed for most populations of the world where H. pylori infection in children and drug resistance are common. Current treatment guidelines do not coincide with the best treatment regimens identified in this meta-analysis.

Keywords Helicobacter pylori, meta-analysis, review, treatments, drug resistance, prevalence, world health, review

Accepted 5 October 2001

Although spiral bacteria were identified on human gastric mucosa as early as 1896,1 it was not until 1982 that Helicobacter pylori was isolated from the stomach of gastritis patients and research into its implications for human health was initiated.2,3 Helicobacter pylori is now recognized as one of the most prevalent bacterial infections in humans.

Evidence suggests that H. pylori infections are acquired primarily during childhood and the infection frequently persists lifelong unless treated. In most of North America and Western Europe, the prevalence of H. pylori increases slowly with age throughout childhood and middle adulthood.4,5 In these populations, large increases in prevalence at older ages are viewed as a cohort effect reflecting increased transmission during childhood in earlier time periods.5 In most of northeastern Asia a similar pattern is observed, but the prevalence dramatically increases with age.6 In much of Africa, Latin America, Eastern Europe, India, and the Middle East, most individuals are infected by adolescence and prevalence remains high throughout adulthood.4,5,7 In a few groups in Malaysia and Australia relatively low prevalence has been reported for all ages.8,9

Helicobacter pylori has been implicated in the aetiology of gastritis, peptic ulcers and gastric cancer.10,11 In 1994, the National Institutes of Health Consensus Development Panel on Helicobacter Pylori in Peptic Ulcer Disease recommended that ulcer patients with H. pylori be treated with antimicrobial agents.11 Treatment to eliminate H. pylori is now considered the most cost-effective method of preventing recurrent peptic ulcers.12,13

Hundreds of studies have evaluated numerous anti-H. pylori therapies. This has left clinicians with the difficult task of discerning which treatments are effective in their patients and which conditions influence effectiveness. Existing practice guidelines for the US, Europe and Asia have been based on pooled global summary estimates,14–18 which can be misleading in the presence of heterogeneity in treatment effects across studies and patient groups.19 Currently, the literature on the effectiveness of H. pylori treatment regimens lacks a meta-analysis which assesses heterogeneity across studies and limits summary estimates to homogeneous patient groups. We conducted this review to identify sources of treatment effect variation and to present summary effect estimates within patient groups that respond similarly to treatment.

Methods

Data sources
We searched for studies with or without placebo groups, using double, triple, or quadruple treatment regimens to eliminate H. pylori from human subjects. Monotherapies were excluded due to their universal ineffectiveness at eliminating H. pylori.20 Sources of studies included: (1) a MEDLINE search for the key words ‘Helicobacter pylori’ (or ‘Campylobacter pylori,’ as it was known previously) and ‘treatment’ for all years prior to 1 January 1999; (2) bibliographies of identified studies; (3) bibliographies of review articles on H. pylori therapy; and (4) unpublished reports. Reports not published as full articles came from: (1) discussion sections and bibliographies of identified studies; (2) abstracts; (3) letters to the editor; and (4) ‘fugitive’ literature.21

Study selection
Inclusion criteria were established a priori to minimize bias in exclusion of studies.22 The review was restricted to treatment groups with the following: (1) a double, triple, or quadruple anti-H. pylori treatment regimen or placebo group (including H2-antagonists [H2-RA] such as ranitidine or cimetidine) given to human subjects; (2) details regarding the name, dosage, frequency, and duration of medications; (3) H. pylori negativity (or elimination) defined as negative results for all detection methods used; (4) the percentage of evaluable subjects known to be infected with H. pylori at baseline who eliminated H. pylori after treatment; (5) information available (at least in abstract form) in English or Spanish; (6) subjects >=18 years of age; (7) subjects not included in previous reports; (8) a consistent regimen used throughout the study; and (9) a treatment group sample size, if reported, of >=5 subjects. We defined a treatment group (treatment arm) as subjects from the same study who were assigned the same treatment protocol. If treatment regimens were used in series on the same patient group, only the first in the series was included. We divided treatment groups by metronidazole resistance status when such information was available. The search for eligible treatment groups ended 1 March 2000. After selecting treatment groups, we excluded regimens used in fewer than three studies since little information beyond that already reported would be obtained for such regimens. Similar regimens were combined into regimen groups (Table 1Go). Placebo or H2-RA groups were examined separately.


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Table 1 Included treatment regimens
 
Study factors
We extracted information on factors that we hypothesized a priori to be potential sources of treatment effect variation.23–27 This included the mean age of subjects, the percentage of males, the number of medications used (2 versus 3–4), and the dosage, frequency, duration of treatment, and characteristics of the local population including the geographical location, the prevalence of infection in children, and the prevalence of metronidazole resistant strains. The prevalence of infection in children was preferred to the overall prevalence as an indicator of current levels of transmission and re-infection.28 (For ease of wording, we will describe patient groups as coming from populations with low or high transmission levels.) If unavailable in the study report, we obtained this information from the literature.

Instead of using quality scoring, which has well-described methodological shortcomings,29–31 we examined the following quality indicators: publication status (full article or other); year of publication or completion; randomized blinded trial (yes/no); post-treatment H. pylori status based on clearance (follow-up test performed within one month of treatment cessation) or eradication (follow-up test performed after one month from treatment cessation); method of determining H. pylori status (histology, culture and urease test on antral and corpus biopsy samples; urea breath test; other); blind assessment of H. pylori status (yes/no); and percentage of subjects not evaluated after treatment. The percentage of subjects not evaluated indicates loss to follow-up and the type of analysis performed (per-protocol or intention-to-treat); zero corresponds to an intention-to-treat analysis.

Definition of treatment effect
We defined treatment effect as the risk difference for eliminating H. pylori in a treatment group versus a placebo group, with risk defined as the probability of eliminating H. pylori. We used the percentage of evaluable subjects known to be infected with H. pylori at baseline who eliminated H. pylori after receiving the intervention to approximate this risk.

Most trials that have evaluated anti-H. pylori therapies are not randomized placebo controlled trials. Randomization with an adequate number of subjects increases the likelihood that treatment groups within a study are similar regarding known and unknown confounders; in other words, it increases the likelihood that groups will have similar background risk. Spontaneous elimination of H. pylori in adults over brief follow-up is rare, thus we expected the probability of eliminating the infection in an untreated group to approximate zero. We tested this hypothesis using the placebo and H2-RA groups to obtain a weighted average of the percentage of infections eliminated without antibiotic treatment. If this background risk approaches zero, then the probability of eliminating H. pylori in any treatment group could be used to estimate the treatment effect. Further, if no infections are eliminated in the placebo group, then confounding cannot occur and the utility of randomization described above does not exist.

Summary estimates of treatment effect and sources of heterogeneity
Estimates of the average effect of a treatment can be misleading if the effect varies systematically across subgroups of patients. We used meta-regression to identify factors influencing the variation in treatment effect and define subgroups of patients responding similarly to treatment.21,22 This allowed us to obtain summary estimates of effect for subgroups lacking any coherent pattern of systematic variation in effect.

We began by examining visual and tabular displays and using Pearson's {chi}2 tests for independence to reveal systematic variation;22 we used exact tests with Monte Carlo estimation for small numbers. We then used a weighted cross-classified multi-level model32,33 to identify sources of variation in the treatment effect across treatment groups, studies and regimen groups. This cross-classified multi-level model was used to account for the structure of the data where treatment groups are found within two distinct hierarchies: studies and treatment regimens. In this meta-regression, the effect of treatment on individual treatment groups (at level 1) was modelled by the random effects of study and regimen group (at level 2) and the fixed effects of study factors listed above.

The sample size, rather than the inverse of the variance, was used as a weight to avoid computing inverse-variance weights from zero cells. When information on the sample size was missing (in five studies), we used the smallest allowable size of 5, thus resulting in a lower weight.

We performed sensitivity analyses by excluding one or more regimen groups at a time and comparing the results to the complete model. We present separate models for regimen groups that notably altered the overall result. In addition, when residual heterogeneity was identified within a regimen group, separate multi-level models were used to examine dosage, frequency, specific duration, specific type of drug, inclusion of proton pump inhibitors or H2-receptor antagonist, geographical location and other factors that might influence the effect of the specific regimen groups. For each regimen group, we calculated weighted mean treatment effects within strata of identified sources of variation.22 When residual heterogeneity was observed, the entire range of observed treatment effects were reported instead of summary estimates. We looked for ‘small study effects' using funnel plots and non-weighted meta-regression.34

Results

Our search identified 618 antimicrobial treatment groups, 25 placebo or H2-RA groups, 32 treatment regimens and 16 regimen groups (Table 1Go). The 618 treatment groups came from studies conducted in 44 countries from 6 continents; western Europe, 66%; US and Canada, 11%; northeastern Asia, 9%; Australia, New Zealand, Singapore and Malaysia, 5%; eastern Europe and the Middle East, 4%; South America, 3%; Africa, 1%; and multiple regions, 1%. Most groups, 80%, were from populations with an estimated prevalence of metronidazole resistance under 40%; nearly all, 89%, came from populations with low transmission levels (4–39% prevalence in children), while just 9% came from populations with relatively high transmission levels (58–94% prevalence in children). Some regimen groups (RMC, RAC, RC, RA, CBO and NCG) were evaluated in less than three studies in high-transmission populations (at least 50% prevalence in children).

Most treatment groups, 82%, were found in published articles; 32% were dual therapies; 4% were treated for <7 days (range 1–6 days), 47% for 7–13 days, and 49% for >=14 days (range 14–42 days); 35%, 9% and 44% of the groups were treated for 7, 10 and 14 days, respectively.

Although 50% of the eligible studies used randomization to assign treatment, only 7% were placebo controlled. The average probability of eliminating H. pylori with a placebo or H2-RA was 0.4% overall (range: 0–4%) and 0% in all studies using either of the two most accurate detection methods (histology, culture and urease test on antral and corpus biopsy samples or urea breath test) in per protocol analyses.35 Because the observed probability of eliminating H. pylori with a placebo approaches zero, we viewed the percentage of infections eliminated in a treatment group as approximating the risk difference.

Heterogeneity across studies
We detected heterogeneity in 12 of the 16 regimen groups. The meta-regression models revealed substantially different sources of heterogeneity when nitroimidazole-based regimen groups were examined separately, and when the AP group was excluded, but did not change appreciably when each of the other regimen groups was omitted. We report the meta-regression results stratified by whether or not the regimen contained a nitroimidazole and separately for the AP group.

Sources of variation in treatment effect
Overall
Triple and quadruple therapies eliminated 33% more H. pylori infections than double therapies. Treatment effect increased with longer treatment duration across regimens. In addition, the effect was relatively low in studies conducted in high-transmission populations, especially with nitroimidazole-based therapies. Unsuccessful elimination in these studies was observed across various frequencies of metronidazole resistance.

Nitroimidazole-based regimens
The effect decreased around 0.5% for every 1% increase in the prevalence of metronidazole resistance. It also decreased with shorter duration of treatment and to a lesser extent in high transmission populations. The effect increased in studies conducted in northeastern Asia (Table 2Go).


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Table 2 Sources of variation in treatment effects
 
Non-nitroimidazole regimens, excluding the AP group
The effect decreased with shorter duration of treatment and more recent year of the report (Table 2Go).

AP regimens
The effect decreased in high-transmission populations or when using a breath test to assess H. pylori elimination. It increased in studies conducted in Germany or northeastern Asia, published as full articles, of longer duration, using clearance or blind assessment to evaluate elimination, with a greater percentage of male subjects, or an increased proton pump inhibitor dosage.

Summary treatment effect estimates
Weighted mean treatment effect estimates and ranges of observed treatment effects appear in Tables 3–5GoGoGo. The highest summary effect estimates for some geographical regions are presented in Table 6Go.


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Table 3 Summary estimates for Helicobacter pylori elimination with nitroimidazole-based regimen groups in populations with a low prevalence of metronidazole resistancea
 

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Table 4 Summary estimates for Helicobacter pylori elimination with nitroimidazole-based regimen groups in populations with a high prevalence of metronidazole resistancea
 

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Table 5 Summary estimates for Helicobacter pylori elimination with non-nitroimidazole-based regimensa
 

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Table 6 Consensus meeting recommended regimens versus alternative regimens identified in this meta-analysis as eliminating Helicobacter pylori in 85% more patients than placebo in identified geographical areas
 
Nitroimidazole-based regimens
The highest treatment effects were observed in northeastern Asia, where reported effects were around 10% higher on average than other geographical regions (Table 2Go). In northeastern Asian populations where transmission levels are low and metronidazole resistance is less frequent, effect estimates over 90% were observed for two 7-day nitroimidazole-based regimens, NCG and MTB (Table 3Go). Outside of northeastern Asia, in populations with low metronidazole resistance and transmission levels, summary effect estimates over 90% include NCG for >13 days and RMC for >=7 days (Table 3Go). The MTB group was effective in most industrialized areas when levels of transmission and metronidazole resistance were low; however, this regimen was ineffective in some treatment groups in England, Norway and populations with high levels of metronidazole resistance or transmission.

Non-nitroimidazole regimens
High treatment effects for 2 weeks of CAP or 7–13 days of RAC were estimated from populations with varying metronidazole resistance (Table 5Go).

Successful regimens by geographical region
In northeastern Asia, clarithromycin-based triple therapies containing either amoxicillin or metronidazole were highly successful. The one-week regimens of MTB and RAC, and the one or two-week regimens of CAP were successful regardless of the level of metronidazole resistance36–43 (Tables 4 and 6GoGo).

The most successful regimens used in the US were (1) CAP given for at least one week; and (2) MTB given for 2 weeks with a gastric acid inhibitor in groups with low levels of metronidazole resistance and transmission. NCG eliminated only 75% to 85% of H. pylori infection in the US when metronidazole resistance and transmission levels were low, while it was highly successful in northeastern Asia or Europe under similar levels of transmission and metronidazole resistance (Table 6Go). The RBC-based regimens were not adequately tested in the US.

In Europe, the most successful regimens used in populations with low levels of transmission and metronidazole resistance: (1) NCG or RMC for one week; (2) NAB for >=2 weeks outside of England; and (3) metronidazole, 500 mg of tetracycline (or oxytetracycline in Norway) four times per day, and a bismuth compound given for either >=2 weeks in Norway, or with a gastric acid inhibitor for 7 days outside of England. Other successful one-week European regimens were: (1) MTB containing 500 mg of tetracycline and metronidazole three times a day in populations with low metronidizole resistance outside of England, and (2) RAC. Clarithromycin-based triple-therapies were more successful in Europe when used in combination with metronidazole, rather than with amoxicillin. In contrast, these regimens were more successful in the US when they contained amoxicillin instead of metronidazole. The CAP, effective in both the US and northeastern Asia, especially when used for >=2 weeks, was less effective in Europe. However, the 2-week regimen was not adequately tested in Europe with doses of clarithromycin greater than 250 mg (Table 6Go).

Relatively low treatment effects were observed in developing countries outside northeastern Asia. The most successful nitroimidazole-based regimen used in non-Asian groups with high metronidazole resistance and low transmission levels was NAG given for >=2 weeks (Table 4Go). In such populations, the treatment effect was slightly greater, just under 80%, for the 2-week non-nitroimidazole-based regimen RA. In groups with high levels of transmission and a low prevalence of metronidazole resistance, only CAP had a treatment effect of at least 80%; one-week, 83% (95% CI : 80, 86); 2-week 93% (95% CI : 92, 95). For populations with high levels of both metronidazole resistance and transmission, the highest summary effect estimate was 68%, observed in Brazilian studies that used a 2-week regimen of MFA.

The effect of small studies
Around 70% of included studies had a sample size less than 50 subjects. MFA was the only regimen where ‘small-study effects' were observed; the treatment effect was 73% (95% CI : 62, 84) for studies with a sample size of <=25, and only 59% (95% CI : 57, 61) for larger studies. This ‘small-study effect’ was not explained by publication status or any of the other quality indicators.

Discussion

This meta-analysis identified the number of drugs given and the treatment duration as major determinants of treatment success variation across treatment groups, studies and regimen groups. In addition, this analysis revealed nitroimidazole-based regimens performed better when used in northeastern Asia or in populations with low levels of metronidazole resistance or transmission. Non-nitroimidazole-based regimens appeared more successful in reports released before 1995, which may reflect an increase in clarithromycin resistance over time.44

Most previous reviews of H. pylori treatment trials reported only tabular data on treatment effectiveness for a small subset of trials,45–54 while some presented pooled estimates of average effect.15,17,25,26,55–60 These estimates, whether adjusted or not, assume an absence of systematic variation in treatment effect across studies or patient groups. Our analysis, and others,26,55,60 identify several sources of treatment effect variation, thus summaries of effects across treatment groups that differ on factors such as treatment duration, prevalence of drug resistance, exposure to sources of re-infection and geographical location are likely to result in misleading estimates that mask important determinants of effect variation.19,21,61 Further, since most reported trials were conducted for >=7 days in populations with a low prevalence of both childhood infection and metronidazole-resistant strains, average estimates from such reviews mask the reduced effectiveness of treatments administered for shorter durations and/or in diverse populations.

Consensus-meeting treatment recommendations for H. pylori have been given for Europe, the US, and Asia (Table 6Go).14,16,18 Although these consensus statements mention duration and metronidazole resistance, they are based on meta-analyses which present pooled estimates of average effect.15,17,55,57–59 In addition, these recommendations appear to be based on reviews that include studies outside of the targeted geographical region, and fail to recognize that treatment effectiveness varies notably by region. Some regimens are endorsed even when they have not been evaluated in the targeted geographical area. Most importantly, these recommendations do not reflect the most successful treatments in these geographical areas within homogeneous patient groups (Table 6Go).

The current meta-analysis, like other meta-analyses, has limitations worth noting. First, due to a lack of information from a substantial proportion of study reports, we were not able to examine compliance, adverse effects, funding source, or patient diagnosis as potential determinants of treatment effect variation. We did include, however, the percentage of subjects not evaluated after treatment, which may be a proxy for severe adverse effects and non-compliance. We were also unable to include the prevalence of clarithromycin resistance due to a lack of data worldwide. Second, aggregate factors, such as the prevalence variables in the meta-regression, estimate the average exposure in populations and may not accurately measure the exposure of individual subjects. Given that the outcome of interest, treatment effect, is also an aggregate measure, the use of these measures is appropriate for inferences regarding the treatment effect in patient groups, although it should be kept in mind that they may not hold for individual patients. Also, some countries have population subgroups whose relevant characteristics deviate from the patient groups examined in this analysis and who may respond differently to treatment.

Lastly, publication bias is a common problem in meta-analyses. The number of H. pylori treatment trials competing for publication is large. Results of successful trials may be published more readily than results of ineffective trials. We attempted to minimize this bias by including results from abstracts, letters, and other reports, but it is clearly harder to find unpublished results. In our meta-regression models we examined how treatment success varied by publication status and observed a 17% (95% CI : –1%, 36%) greater probability of successful elimination for published versus unpublished reports in the largest regimen group (AP). Although we cannot be sure if the inclusion of unpublished studies actually increased or decreased publication bias,62 without their inclusion we could not estimate the effect of publication status on the variation in treatment effect across studies. Additional potential for publication bias may have arisen by excluding reports written in languages we could not read. Although many non-English journals include abstracts in English, some do not. If results from less successful treatment groups were frequently published in those that do not, then publication bias would have occurred. Such publication bias may explain the observation that nitroimidazole-based regimens performed better in northeastern Asia than in other regions of the world and that some were successful regardless of the prevalence of metronidazole resistance. However, only one study from northeastern Asia was excluded due to language, therefore such bias is unlikely. The 16 other studies excluded due to language came from Europe; including 8 from Germany. Exclusion and publication biases may explain the higher success of the AP therapy in Germany compared to other geographical regions outside of northeastern Asia.

Even though most worldwide H. pylori infections occur in areas of the world where the prevalence in children is high, only a small fraction of treatment studies were conducted in such areas. In such populations, we observed low treatment effects across regimens, even when metronidazole resistance was not high. Further evaluation of treatment regimens in these settings is needed.

Conclusions

Helicobacter pylori treatments that are highly effective in patient groups from developed countries, where current levels of transmission and metronidazole resistance are low, cannot be presumed to perform well in patient groups from other settings. Examination of sources of variation in treatment success highlights the lack of successful treatments for the majority of the world's infected population. Future research should be aimed at improved treatment for the largely overlooked populations of the less developed areas of the world.

Consensus-meeting treatment recommendations do not accurately reflect the most successful treatments in the targeted areas within groups responding similarly to treatment. Furthermore, treatment recommendations are lacking for geographical areas where most H. pylori infections occur (Africa, South and Central America, Eastern Europe, India, and the Middle East), and where childhood infection and metronidazole resistance are common.

Acknowledgments

We would to like thank Sander Greenland, David Forman, John Walsh, Barbara Visscher, Elisa Priest, Anne Coulson, Lawrence Ash, Jorge Vargas, Margaret Caughy, Raul Caetano, Arnold Schecter, Carrie Peterson Jones, Matthias Egger and the anonymous reviewers for their helpful comments on earlier drafts of this manuscript. The Wiseman Fund supported photocopying costs for this project.

Notes

For a complete list of data sources, contact Dr Fischbach or see: http://swnt240.swmed.edu/publichealth/studieslf.htm

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