Challenges in the Treatment of Recurrent Overt HE

Arun B. Jesudian, MD: Steve, I think you were involved in some of these trials, the landmark trials, of rifaximin and in combination with lactulose. Can you give us an idea of how efficacious that combination [is] in patients with overt hepatic encephalopathy, preventing recurrence, preventing hospitalizations, things like that?

Steven L. Flamm, MD: It’s a great question, Arun, and very, very critical to the appropriate management of these sick patients. First of all, rifaximin’s approved usage is not actually what we discussed yet. It is not approved at this point for treatment of acute overt encephalopathy. Now at Northwestern [University Feinberg School of Medicine], when a patient has overt encephalopathy, we treat the precipitating factor correction, and lactulose, the ammonia-reducing agent, and when the patient is starting to get better we start them on rifaximin, in the hospital, every patient. But it’s not yet for treatment of the overt episode. It’s for prevention of recurrence.

The pivotal trials that led to the approval of rifaximin in this disease space were specifically in patients that had had multiple bouts of encephalopathy, at least 2 within 6 months of presentation, and were at their baseline when the study began. And the idea was not to treat acute overt HE because they were at their baseline. It was to prevent recurrence in a high-risk population. And the study was a placebo-controlled study [in which] patients received rifaximin versus placebo for 24 weeks in this high-risk population.

Now it turned out that about 90% of the patients in both groups were also on lactulose. So essentially this was a study that looked at lactulose and rifaximin versus lactulose alone, with placebo, for prevention of recurrence in high-risk patients. And from the [adverse]-effect part, which you were just discussing, rifaximin really did not have [an adverse]-effect difference from placebo really in anything of note during the 6-month placebo-controlled trial.

And this is a testimony to the safety of the product used over the long term in this patient population. And that includes C diff [Clostridium difficile]. There were 2 patients, 2 cases of C diff reported in the study in the rifaximin group. But both patients had other causes of C diff. Both patients were treated successfully for C diff and were maintained on the rifaximin throughout the course of their C diff and resolved it.

It’s not my knowledge that really anybody believes that C diff is related to rifaximin. And so in our sick-patient population, this is a very safe product. And one other thing. Since it’s so minimally absorbed, you don’t need to have any dose reductions or dose considerations in either patients with liver failure, which our patients have, or renal failure, which many of our patients also have. That’s actually an important consideration for this product when being used by health care practitioners. So we can talk more about the efficacy whenever we get to that part.

Arun B. Jesudian, MD: Sure. And so you would feel comfortable using rifaximin in your sickest patients, your Child-Pugh [Class] C cirrhotics or very high-meld patients. Does that worry you at all?

Steven L. Flamm, MD: That’s a great question too. In the pivotal study, the highest meld score, I believe, was up through 24. I believe patients with a meld score of 25 and higher were excluded, so there weren’t many Child-[Pugh Class] C cirrhotics in the study. And in fact, rifaximin does have a slightly increased absorption in patients with very, very advanced liver disease. And yet in practice, we use it all the time in patients [who] are Child-[Pugh Class] C for prevention of recurrence. And I’ve not personally experienced an issue with it, nor have I heard anyone else either, nor have I seen any literature to the effect that there have been any clinical implications of using rifaximin in patients with Child-[Pugh Class] C. What about you, Arun or Elliot? Have you seen any issues?

Arun B. Jesudian, MD: No, that’s my experience as well. It’s a question that I sometimes get asked. And the way I usually answer it is that in every transplant center I know of, those sickest patients are usually on rifaximin. Almost all of them have HE, and I’m not aware of anyone reporting an adverse outcome related to it and based on severity of liver impairment. Elliot, [are] you?

Elliot B. Tapper, MD: Yeah, I have to agree. You know, there’s the population enrolled in clinical trials that’s obviously different from [what] we see in the real world. But we have adequate real-world studies of rifaximin, and adequate real-world experience to confirm that. In fact, when we’ve extrapolated those results to the sickest possible patients, it remains safe and effective.

Transcript edited for clarity.