COMMENTARY

A Promising New Treatment Option for IBS

David A. Johnson, MD

Disclosures

January 11, 2011

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Hello. I'm Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Irritable bowel syndrome (IBS) is a very common condition. We see this frequently in clinical practice. Population-based studies suggest that IBS affects 10%-20% of the population. The treatment of IBS, however, is somewhat frustrating, primarily because the pathophysiology is not well understood. In fact, multiple factors are suggested, and more than likely IBS patients are a very heterogeneous population, with multiple factors operating in each patient.

A lot of interest has focused recently on the potential microflora of the gut being 1 of the key factors causing IBS symptoms. A number of studies have shifted focus toward the changes in microflora perhaps influencing the outcomes of patients with IBS. There have been a lot of studies focusing on the use of probiotics to change the microflora itself. These have been fairly mixed, with not great results, but still somewhat promising.

Perhaps more promising were the previous studies that looked at the effects of antibiotics. These studies have been relatively small. The most promising studies have involved rifaximin, a poorly absorbed antibiotic that has been previously used for traveler's diarrhea, and is now approved for hepatic encephalopathy. The studies that have been favorable have been fairly small and limited by questions about statistical analyses and choice of primary endpoints.[1]

Enter into the present data a very promising evaluation. Two parallel studies were combined in a report of 1260 patients in the most recent issue of the New England Journal of Medicine.[2] These 2 studies were deemed TARGET 1 and TARGET 2. These 2 studies involved patients with nonconstipation IBS in double-blind randomized prospective evaluations of a 2-week course of rifaximin 550 mg 3 times daily for 2 weeks, with follow-up extending for 10 weeks beyond the course of therapy.

Rifaximin is a poorly absorbed antibiotic. It's an extremely effective drug for both gram-positive and gram-negative bacteria and also for anaerobes, in particular, Clostridium difficile.

The study had patient-centered outcomes. Patients were queried every week about their symptoms. The endpoints were binary; the primary endpoint was a yes/no response to global IBS symptoms -- were the symptoms better or not at 2 weeks following the initiation of the therapy and then over the course of the next 10 weeks of therapy? The P value here was .001 with a margin of 9% for the 2 trials combined. The secondary endpoint was relief of IBS bloating symptoms, again, with a binary endpoint, yes or no. The P value again was .001 and the margin here was 10%.

Now we have 2 parallel, very well-done studies, grouped together, and showing improvement in the 9%-10% range for global symptoms and bloating following treatment of IBS (nonconstipation-related). The number needed to treat for this therapy would be approximately 9-10 -- a very reasonable number for therapeutic efficacy, considering that this is a disease for which we have not had good treatments.

Why would rifaximin work? Much still remains to be defined about whether it's the microflora changing and the effect of microflora on degradation of food products or biologic products in the gut itself, or whether the change in microflora may influence the gut through its secretions or involvements in the gut immune system and the gut post-response. We don't have a specific answer, but it may be a combination of both.

Nonetheless, we have a treatment effect in a study that was very well defined, with strong endpoints, and patient-centered outcomes that occurred, at least in follow-up, until 10 weeks after the primary treatment. Questions remain about how long this will last. What's the effect of re-treatment? Are there any real side effects of long-term use of this antibiotic? One limitation of this approach might be the cost, because at present this is a fairly expensive drug. We've had very limited success with a number of other therapeutic interfaces for IBS.

It remains to be seen if we can better select patients for this therapy, so that would be a key factor for future studies. Are there any predisposing factors that can be identified to help us better use a fairly expensive, but effective, course of therapy? What is the long-term effect of use of an antibiotic on the population? At present, what am I doing in my practice? We've added a new arrow to the quiver of treatment for IBS. Our traditional therapies may certainly be a lot more cost effective at present, at least for the short term. We should perhaps reserve this new therapy for the patient who has gone through and failed other therapies, and use this very promising therapy for nonconstipation IBS.

Hopefully these studies will be followed up and the extended evaluation of these patients will be offered to us in future reports, but for the present we have a new opportunity for treatment of IBS. I'm Dr. David Johnson. Thanks for listening.

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