By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH
Dr. Watkins reports no financial relationships relevant to this field of study.
SYNOPSIS: A Phase III, randomized, controlled trial found a significantly higher eradication rate for H. pylori with a 14-day regimen of rifabutin, amoxicillin, and omeprazole compared to 14 days of amoxicillin and omeprazole.
SOURCE: Graham DY, Canaan Y, Maher J, et al. Rifabutin-based triple therapy (RHB-105) for Helicobacter pylori eradication: A double-blind, randomized, controlled trial. Ann Intern Med 2020;172:795-802.
The treatment of Helicobacter pylori, the most common cause of peptic ulcers and gastric cancer, has become more challenging because of the spread of antibiotic resistance. Indeed, several antibiotics that were previously used empirically, such as clarithromycin, metronidazole, and levofloxacin, are no longer effective in many cases. Previous studies have shown that rifabutin is active in vitro against H. pylori, and resistance is slow to develop. After promising results from a pilot study, Graham and colleagues conducted a clinical trial to compare a treatment regimen that contained rifabutin to a standard combination for eradicating H. pylori.
The study was a Phase III, double-blind, randomized, controlled clinical trial that enrolled adults with dyspepsia and confirmed H. pylori infection. Patients were randomly assigned in a 1:1 ratio to receive a fixed dose combination of amoxicillin 3 g, omeprazole 120 mg, and rifabutin 150 mg (AOR) or amoxicillin plus omeprazole (AO), four capsules every eight hours for 14 days. A follow-up 13C urea breath test was performed at the test-of-cure visit (conducted between days 43 and 71 after initiation of treatment) to determine H. pylori eradication. Plasma concentrations of the drugs were measured at baseline and at day 13 visits. Also, pharmacogenetic testing was done at baseline to assess the status of CYP 2C19, which is the liver enzyme that metabolizes omeprazole. Exclusion criteria included prior H. pylori treatment; alarm symptoms (e.g., anemia, melena, weight loss, or dysphagia); more than two active gastric or duodenal ulcers; a history of esophageal or gastric surgery; previous gastric cancer; and recent receipt of antibiotics, a proton-pump inhibitor, or a bismuth-containing medication. Also, persons of Asian descent were excluded because of concerns about polymorphisms in cytochrome P450 genes that can affect omeprazole metabolism.
Two hundred twenty-eight patients received AOR and 227 received AO. The treatment groups were well-balanced in terms of demographic characteristics. The mean age was 46.5 years (standard deviation [SD], 13), 62.2% were women, and 60.0% were Hispanic. At baseline, 22 (6.4%) of the patients were infected with amoxicillin-resistant H. pylori strains. No isolates were resistant to rifabutin. The mean adherence rate, determined by pill counts, was 97.5% (SD, 14.2%) in the AOR group and 97.9% (SD, 13.1%) in the AO group.
The eradication rate was higher in the AOR group compared to the AO group (83.8%; 95% confidence interval [CI], 78.4% to 88.0% vs. 57.7% [95% CI, 51.2% to 64.0%], respectively; P < 0.001). Interestingly, the eradication rate with the AOR regimen was high even for strains that were resistant to amoxicillin (80%), but predictably was much worse for the AO regimen (25%). The rates of adverse events were similar between the two groups, with diarrhea and headache more common in the AOR group vs. the AO group (10.1% and 7.5% vs. 7.9% and 7.0%, respectively), while nausea, abdominal pain, and dizziness were more frequent in the AO group. More rashes were seen with AOR (1.3%) than with AO (0). Finally, no adverse events were found to be related to the CYP 2C19 genotype.
The dwindling number of effective drugs to treat H. pylori infection is an increasing concern. In the United States, there has not been a new therapy approved by the Food and Drug Administration to treat H. pylori since 1997. Therefore, the study by Graham and colleagues is welcome since it provides evidence for the effectiveness of a novel, fixed-combination regimen. Another highlight was that the adherence rate, tolerability, and adverse event profile of the three-drug regimen compared favorably to the two-drug regimen. Moving forward, it will be important to see how much the novel regimen will cost and if the rate of adverse events will remain low once it becomes widely prescribed. Moreover, while none of the H. pylori strains demonstrated rifabutin resistance, this undoubtedly will occur with increasing use and will need to be recognized and monitored by clinical microbiology laboratories.
Despite the robust design, there are a few limitations to the study that deserve mention. First, since the investigators excluded people of Asian descent, it is not clear if the drug will be safe and effective for this group of patients. Second, there were limited data on the clinical breakpoints for the amoxicillin-resistant strains. Third, quadruple therapy that includes bismuth is the regimen prescribed most frequently for H. pylori in the United States. How AOR would compare to this regimen is unknown. Finally, all of the clinical sites were in the United States, so the results might not be applicable to other geographic areas.
A new combination treatment option for H. pylori infection appears to be on the horizon. Although it is a cause for optimism, whether the results from the randomized clinical trial will hold up in real-world settings remains to be elucidated. Further studies that compare AOR to current first-line regimens also seem warranted.