Andrea Tampieri

Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: A Randomized Trial

Context Eradication rates for Helicobacter pylori infection are decreasing worldwide because of increasing antimicro-bial resistance. Contribution This double-blind trial randomly assigned 300 adults with dyspepsia or peptic ulcers to a 10-day sequential regimen (pantoprazole, amoxicillin, and placebo taken for 5 days followed by pantoprazole, clarithromycin, and tinidazole taken for 5 days) or standard 10-day therapy (pantoprazole, clarithromycin, and amoxicillin). The eradication rate of H. pylori infection was greater with the sequential regimen (89%) than with the standard treatment (77%). Approximately 5% of patients in each group had epigastric pain and 3% to 5% had mild diarrhea. Implication Sequential therapy eradicates H. pylori infection more often than does standard therapy. The Editors Helicobacter pylori infection causes peptic ulcers, gastric mucosaassociated lymphoid tissue lymphoma, and gastric cancer (1). Standard treatments for H. pylori infection that have been endorsed by U.S. and European authorities rely on clarithromycin or metronidazole in conjunction with other antibiotics and acid inhibitors (2, 3). The prevalence of clarithromycin and metronidazole resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection (4). Eradication rates in most western countries have declined to unacceptable levels. Eradication therapy fails in approximately 1 in 5 patients (5). A simple, short treatment regimen that would return eradication levels to those seen at the advent of H. pylori treatment is urgently needed (5). Such a regimen should have high efficacy against clarithromycin-resistant and metronidazole-resistant strains of H. pylori because these strains are increasingly encountered in routine clinical practice. Novel 10-day sequential therapy consisting of 5-day dual therapy (proton-pump inhibitor plus amoxicillin) followed by 5-day triple therapy (proton-pump inhibitor, clarithromycin, and tinidazole) has had good eradication success in unblinded trials in elderly and pediatric patients (68). However, no double-blind, controlled trials using conventional therapy have been reported, and the effect of clarithromycin and metronidazole resistance on the outcome of sequential therapy has not been studied prospectively. The aim of this study was to compare a 10-day sequential treatment regimen for H. pylori infection with standard 10-day triple therapy in a randomized, controlled trial. Secondary objectives were to determine the efficacy of the treatment regimen in patients with resistant strains of H. pylori, to assess treatment adherence, and to evaluate side effects. Methods Design Overview This was a prospective, double-blind, controlled study with a parallel-group design. At baseline, patients were evaluated for inclusion and exclusion criteria and provided written informed consent. Patients were then randomly assigned to a treatment group and had follow-up evaluations to assess the eradication rate of H. pylori infection, treatment adherence, and side effects. The study was performed according to good clinical practice and the Declaration of Helsinki. The ethics committees at the 2 participating centers approved the study. The consent form indicated that patients would be randomly assigned to treatment that was the current standard or a new therapy that might have higher eradication rates. Patients were told that eradication failure was possible with any therapy regimen. All patients with eradication failure were offered a rescue therapy on the basis of the results of sensitivity testing. Setting and Participants Between September 2003 and April 2006, consecutive patients with dyspepsia who were at least 18 years of age, who had never received treatment for H. pylori infection, and who had been referred to our hospitals (Bologna, Italy, and Rome, Italy) for a gastroenterology consultation were asked to participate in the study. No special recruitment techniques (such as advertisements or letters sent to primary care physicians) were used. Exclusion criteria were previous treatment for H. pylori infection; use of proton-pump inhibitors, H2-receptor antagonists, bismuth preparations, or antibiotics in the previous 2 weeks; concomitant use of anticoagulants or ketoconazole (because of potential interaction with the nonsteroidal anti-inflammatory drugs) and glucocorticoids (because of association with ulcer disease); the ZollingerEllison syndrome; previous surgery of the esophagus or upper gastrointestinal tract (except appendectomy, polypectomy, or cholecystectomy); severe or unstable cardiovascular, pulmonary, or endocrine disease; clinically significant renal or hepatic disease or dysfunction; hematologic disorders; any other clinically significant medical condition that could increase risk; malignant disease of any kind except for successfully treated skin cancer (basal- or squamous-cell carcinoma) during the previous 5 years; Barrett esophagus or high-grade dysplasia; drug, alcohol, or medication abuse within the past year; severe psychiatric or neurologic disorders; and pregnancy or lactation, as well as sexually active women of child-bearing years who were not willing to practice medically acceptable contraception (oral or injectable contraceptives, implantable or mechanical intrauterine or vaginal devices, or vasectomy for the partner) for the study duration. Randomization and Interventions Patient allocation was determined with a random-number chart that was concealed from investigators and patients by using numbered blister packs of the study medication that corresponded to the random-number chart. A computer-generated randomization chart was used to determine allocation, which was stratified according to center by using a block design and a block size of 4. Allocation was concealed with an opaque envelope, which contained a number that corresponded to the numbered blister packs. The envelope was opened when the patient met the inclusion criteria and provided informed consent. Patients and investigators were blinded to treatment group. Patients were randomly allocated to receive a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, and placebo, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days); or standard therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily for 10 days). Medications were contained in individual blisters in the package. A placebo that was identical in color and shape to the clarithromycin capsule was administered during the first 5 days of sequential therapy to maintain blinding. This ensured that all patients took 3 medications twice a day for 10 days. Measurements and Outcomes The primary outcome of the study was eradication of H. pylori infection. Secondary outcomes were to determine the efficacy of sequential treatment against clarithromycin-resistant strains of H. pylori, to assess adherence to therapy, and to determine the frequency of self-reported side effects. 13C-Urea Breath Test Urea breath tests were done after an overnight fast. A baseline breath sample was obtained, and 75 mg of 13C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 minutes after the test solution was administered. The results of the test were considered positive if the difference between the baseline sample and the 30-minute sample exceeded 4.5 parts per 1000 of 13CO2. All breath samples were analyzed in Bologna by using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany). The accuracy of the urea breath test was previously validated in our laboratory. We reported sensitivity and specificity values of 94.7% and 95.7%, respectively (9). Endoscopy All patients with positive results on the urea breath test had upper endoscopy, and 5 biopsy specimens were obtained during the procedure. Two specimens were taken from the antrum and 2 were taken from the corpus for histologic evaluation. The specimens were stained with hematoxylin and eosin and Giemsa stains, and gastritis was scored by using the updated Sydney System (10). The pathologist who performed the histologic examination was blinded to the results of all other tests. One biopsy specimen was obtained from the antrum for the rapid urease test (Campylobacter pylori test, Yamanouchi Pharma S.p.A, Corrugate, Milan, Italy). Two additional biopsy samples from the antrum were collected for bacterial culture and susceptibility testing. We performed cultures without knowing the other test results. For this purpose, biopsy specimens were sent to a single microbiological laboratory in Bologna within 24 hours and were stored at 70C. Isolated strains were tested for primary clarithromycin and metronidazole resistance by using an agar dilution method, which was defined as a minimal inhibitory concentration greater than 1 mg/L and greater than 8 mg/L for clarithromycin and metronidazole, respectively (11). Strains were classified as having isolated resistance to clarithromycin or metronidazole if the organisms were only resistant to 1 antibiotic. Dual resistance was defined as resistance to clarithromycin and metronidazole. At baseline, patients were classified as having H. pylori infection if the results on the urea breath test were positive and if the results on at least 2 of the following 3 tests were positive: rapid urease test, histologic examination, and culture. An expert panel recommended these criteria for use in clinical trials of H. pylori infection (12). Follow-up Procedures Treatment Adherence and Side Effects Patients were asked to return at the completion of therapy for a physical evaluation and to assess adherence to therapy and side effects. We first aske

High eradication rates of Helicobacter pylori with a new sequential treatment

Background : Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance.

A 10-day levofloxacin-based triple therapy in patients who have failed two eradication courses

Background : A standard third‐line treatment is lacking, and European guidelines recommend performing culture in these patients. However, the use of this procedure as ‘routine practice’ is definitively not feasible.

Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection.

OBJECTIVE:There is uncertainty about the best method of testing patients for Helicobacter pylori (H. pylori) infection while they are taking proton pump inhibitors. The aim of this study was to determine: (i) if the decreased sensitivity of the urea breath test during proton pump inhibitor is corrected by different techniques for breath testing and (ii) if the sensitivity of stool test is decreased with the administration of proton pump inhibitors.METHODS:Prospective randomized single-blind study was performed in a tertiary care university hospital. Out of 72 H. pylori infected patients endoscoped for upper abdominal symptoms 48 were randomized to proton pump inhibitors (omeprazole 20 mg each day or esomeprazole 40 mg each day) and 24 to antacid (aluminum hydroxide 800 mg each day) for 14 days. Several breath tests (standard 75 mg 13C-UBT with citric acid, with orange juice, a tablet breath test with 100 and 50 mg of 13C), and a stool test were carried out. Baseline samples were collected before and after treatment.RESULTS:The baseline sensitivity for all breath tests was 100% in both groups; for stool test it was 97.8% (95% CI: 88.7–96.6) and 90% (95% CI: 69.9–97.2) in the proton pump inhibitor and antacid group, respectively. After treatment, the sensitivity of tests was significantly low (UBTs range: 77.1%–85.4%; stool test: 83%; 95% CI: 63.9–91.1), while it was unchanged in the antacid group.CONCLUSIONS:False negative breath and stool tests are equally common in patients taking proton pump inhibitors. Antacids do not impair the sensitivity of the breath tests or the stool test.

The clinical role of cytochrome p450 genotypes in Helicobacter pylori management

OBJECTIVE:The aim of this pharmacogenomics study was to investigate the influence of different cytochrome P450 (CYP) genotypes in Helicobacter pylori eradication therapy.METHODS:The study involved 143 consecutive Italian Caucasian patients with H. pylori infection diagnosed and treated with 1-wk triple therapy according to European Helicobacter Pylori Study Group guidelines. Using human genomic DNA, CYP2C19 (*2 and *3) and CYP3A4 alleles (*1B, *2, and *3) were evaluated by polymerase chain reaction–restriction fragment length polymorphism assays and confirmed by sequencing the amplicons.RESULTS:According to the endoscopy-based gold standard, 93 patients achieved H. pylori eradication. Regarding CYP2C19 genotype, the 50 patients who remained infected were all homozygous or heterozygous extensive metabolizers (homEM or hetEM). Carriers of homEM fared significantly less well than those of hetEM; homEM genotype was also predictive of failure at univariate/multivariate analysis. Carriers of CYP3A4 polymorphisms achieved favorable eradication rates similar to patients bearing CYP2C19. All four patients with single CYP3A4*2 polymorphism achieved eradication, and only 29% (5/17) of all CYP3A4*1B carriers did not achieve eradication. All nine patients carrying CYP3A4 polymorphisms in the CYP2C19 hetEM subgroup were cured, suggesting the possibility of a positive synergism between CYP3A4 and CYP2C19.CONCLUSIONS:This first pharmacogenomics study on the influence of different CYP genotypes on H. pylori therapy suggests that, as in Asian populations, CYP2C19 genotype patterns are probably also relevant in Caucasians receiving H. pylori eradication regimens that include omeprazole. The possibility of a favorable drug interaction mediated by CYP2C19 and CYP3A4 requires investigation.

A rapid, low‐dose, 13C‐urea tablet for the detection of Helicobacter pylori infection before and after treatment

Background : A new urea breath test (UBT) has been described which uses a tablet formulation of 13C‐urea with citric acid and allows breath sampling to be performed as early as 10 min after ingestion of the tablet.

Accuracy of breath tests using low doses of 13C-urea to diagnose Helicobacter pylori infection: a randomised controlled trial

Background: The 13C-urea breath test (UBT) for detecting Helicobacter pylori infection is a non-invasive method based on the organism’s urease activity. Since its first description, the method has been extensively modified. However, only the dose of 13C-urea and the measurement equipment are directly related to the cost of the test. Aims: (1) To assess the diagnostic accuracy before eradication therapy of three UBTs using 25, 15, and 10 mg of 13C-urea, respectively; and (2) to determine diagnostic performance in the post-eradication setting showing the highest values for sensitivity and specificity with the lowest dose of 13C-urea. Methods: Three hundred consecutive patients were randomised to be tested with one of the three UBTs. All patients underwent upper endoscopy with biopsies. A total of 222 more patients were enrolled to evaluate the second aim. Infected patients were offered treatment and asked to return 4–6 weeks after the end of therapy to perform endoscopic follow up and to carry out 13C-UBT. Results: In the pretreatment setting, 13C-UBT 25 mg had a sensitivity of 100% (95% confidence interval (CI) 91.8–100) and a specificity of 100% (95% CI 93.7–100); 13C-UBT 15 mg had a sensitivity of 96.1% (95% CI 86.8–98.9) and a specificity of 100% (95% CI 92.6–100); and 13C-UBT 10 mg had a sensitivity of 89.1% (95% CI 77–95.3) and a specificity of 100% (95% CI 93.3–100). As the test with the best performance and the lowest dose of 13C-urea was 13C-UBT 15 mg, it was evaluated after treatment, reporting a sensitivity of 100% (95% CI 79.6–100) and a specificity of 98.9% (95% CI 94.3–99.8). Discussion: UBTs using 25 and 15 mg of 13C-urea were both accurate in the diagnosis of H pylori infection in untreated patients. 13C-UBT 15 mg was also accurate for follow up of patients after treatment.

Serological markers for gastric atrophy in asymptomatic patients infected with Helicobacter pylori

OBJECTIVE:Atrophic gastritis is a precancerous condition that is commonly caused by chronic Helicobacter pylori (H. pylori) infection. This blinded, controlled study was designed to determine if serum gastrin and pepsinogens were reliable markers of atrophy in asymptomatic patients.METHODS:One hundred and forty-seven asymptomatic patients underwent endoscopy with multiple gastric biopsies obtained for histology, culture, and rapid urease test. Fasting serum gastrin (total and G-17) and serum pepsinogens (I-II) were determined by standard immunoassays. Gastric atrophy was histologically assessed in accordance with internationally accepted criteria; three main patterns of gastritis were distinguished: (a) nonatrophic gastritis, (b) atrophic antrum-restricted and antrum-predominant gastritis, and (c) corpus-restricted gastritis. Receiving operating characteristic (ROC) analysis was used to determine the best cut-off for each serum test in nonatrophic gastritis versus antrum-restricted/antrum-predominant atrophic gastritis.RESULTS:No significant differences in serum gastrin and pepsinogens I-II were detected in nonatrophic gastritis versus patients with antrum-restricted/antrum-predominant atrophic gastritis. The positive likelihood ratios for an abnormal serum test to detect antrum-restricted/antrum-predominant atrophy in the gastric body were total serum gastrin 2.13 (95% CI 0.99, 4.6), gastrin-17: 1.55 (95% CI 0.75, 36.17), pepsinogen I: 2.74 (1.4, 5.4), pepsinogen II: 1.74 (1.27, 2.39), and the ratio of pepsinogen I and II: 1.8 (1.2–2.8). Negative likelihood ratios ranged from 0.20 to 0.65.CONCLUSIONS:In an asymptomatic population, serum gastrin (total and G-17) and pepsinogens I-II (and their ratio) do not discriminate nonatrophic versus antrum-restricted/predominant atrophic gastritis.

A rapid immunochromatographic assay for Helicobacter pylori in stool before and after treatment.

Background : Current guidelines recommend non‐invasive testing and treatment of young dyspeptic patients without alarm symptoms.

Helicobacter pylori infection from pathogenesis to treatment – a critical reappraisal

The main areas of this review are Helicobacter pylori and disease pathogenesis; the relationship of H. plyori to lower gastrointestinal diseases, liver disease and extra‐gastrointestinal conditions; the relationship of H. plyori to gastro‐oesophageal reflux disease; infection in the very young and very old; diagnostic techniques; and management of H. plyori infections with particular emphasis on eradication regimens and antibiotic resistance.