Gut Check: H pylori Part 2—Treatment

In part 2 of their podcast on Helicobacter pylori, Drs William Chey and Brian Lacy talk about the risks of untreated disease and the various types of treatment available.

Brian Lacy, MD, is a professor of medicine at Mayo Clinic in Jacksonville, Florida. William D. Chey is a professor of medicine at the University of Michigan in Ann Arbor, Michigan.

TRANSCRIPT:

Any views and opinions expressed are those of the author, and/or participants, and do not necessarily reflect the views policy or position of Gastroenterology Learning Network or HMP Global, their employees, and affiliates.

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. And I am absolutely delighted to be speaking today with Dr. William Chey, section chief and professor of medicine in the Division of Gastroenterology and Hepatology at the University of Michigan in Ann Arbor, Michigan. For those listening in today, you may recall there was a prior podcast discussing the prevalence, the impact, and the diagnosis of H. pylori.

So, welcome back for our older listeners, and welcome to our new listeners. Today we're going to discuss the treatment of H. Pylori, which is this incredibly prevalent infection of the stomach, both worldwide and in the United States. So Bill, welcome back. Thank you for joining us again today. As I mentioned in the introduction, we discussed the epidemiology and risk factors and consequences of H. Pylori. But for today, let's focus on treatment. To begin, which patients should be treated? Does everyone with H. pylori need treatment?

Dr William Chey:

Brian, this is an important question. This may be an unusual answer that you don't expect. And this is what I would say is that the way to think about this is that you need to link diagnosis and treatment. So if you feel that somebody has an indication for a treating H. pylori, then test them for H. pylori. But on the other hand, if you have questions about whether it's appropriate to treat the H. pylori if you find it, then don't do the test. So the classic indications are those—won't be surprising to the audience—things like peptic ulcer disease, things like uninvestigated or functional dyspepsia, patients that are starting chronic therapy with NSAIDs or aspirin, ITP, idiopathic, thrombocytopenic purpura, or unexplained iron-deficiency anemia. These are all accepted indications for H. pylori therapy at this point.

The one that people may not necessarily think of, but is very important, are individuals with a family history of gastric cancer. Remember that individuals with a family history of gastric cancer are, A, at much higher risk, significantly higher risk, of developing gastric cancer, and, B, also at a significantly higher risk of being infected with H. pylori infection. So remember that H. pylori is a class 1 carcinogen for gastric adenocarcinoma. And there is data—although it's controversial—there is data that eradication of H. pylori infection might decrease the risk of developing gastric cancer, particularly in individuals who have not yet developed intestinal metaplasia. So early H. pylori infection, eradication of that significantly reduces the risk of developing gastric cancer. There is probably a point of no return beyond which eradicating H. pylori offers little benefit, unfortunately.

Dr Brian Lacy

Bill, great answer. And thank you for putting that in perspective. So thinking about treatment, bismuth is used in some protocols. And bismuth is a really interesting agent. You know this, but the medical history is kind of interesting, meaning it was officially discovered in about 1753. It's been used for medical purposes since the Middle Ages. And Louis Odier was credited for using it to treat dyspepsia as early as 1786. And it was used to treat severe diarrhea and cholera in the United States in the early 1900s. But when we think about bismuth, what's the mechanism of action for treating H. pylori?

Dr William Chey:

It remains a bit of a mystery. Bismuth does a lot of things, so it definitely has antimicrobial properties and broad antimicrobial properties, which is probably why it's very good for things like traveler's diarrhea. But it also forms complexes with bacterial wall and the periplasmic space, which inhibits a variety of different enzymes, which may be relevant to its antibacterial properties.

Dr Brian Lacy

Wonderful. And so as a segue there, thinking about antimicrobial properties and antibiotics, when we start thinking about treatments and the use of antibiotics, it's important to understand antibiotic-resistance patterns in the United States. And should we just assume that in different parts of the country it's all equal? Do we assume people are antibiotic-resistant? Do we need to check? Or do we just not worry about this at all?

Dr William Chey:

Yeah, and let me just start the answer to that question by saying that bismuth is such an interesting compound, because there's no such thing as, at least that I know of, a bismuth resistance, related to the fact that it's at least in part acts by interacting with bacterial surface proteins, as opposed to an actual antibiotic effect, like things like penicillin or ciprofloxacin, et cetera. Resistance is much less of an issue. In fact, I don't think it's an issue at all with bismuth, which makes it very attractive for an infection like H. pylori infection.

As to the second part of the question that you asked about, antibiotic resistance, antibiotic resistance is probably the most important factor in terms of determining the effectiveness or ability of a regimen to eradicate H. pylori infection. It's not to say it's the only factor. And that's a mistake. It's a pitfall I think that we all fall into. We think that if we just choose antibiotics purely on the basis of its susceptibility, that means that the regimen will always work. Unfortunately, that's not true. But it is true that choosing an antibiotic regimen on the basis of susceptibility increases the likelihood of achieving eradication. So it is an important factor, but it's not the only factor.

Now, antibiotic resistance has been a moving target, and it will remain a moving target, because it's highly influenced, not only by the genetics of your population, and think about the genetics of our population in the United States, remarkably heterogeneous and growing more and more heterogeneous by the day, but not just genetic factors, but also antibiotic exposure. So it's been found that one of the most potent predictors of antimicrobial resistance for H. pylori, and this is probably true of virtually any infection, is related to the number of exposures that an individual has had to that antibiotic for any reason.

So let's say that Joey at age 8 got a course of clarithromycin for a sore throat. That increases Joey's risk of having a resistant strain of H. pylori infection when you see them as an adult. And the more times he or she has seen a macrolide, a quinolone, the more likely he or she is to harbor a resistant strain of H. pylori infection to that antibiotic. So, it matters a lot. Right now, if you think about it, you might be asking yourself, "Well, if it's so important, why is it that we treat purely empirically the antibiotics for H. pylori infection in the United States?" and by the way, in really most of the world right now. It's because there's not widely available, easily accessible antibiotic-sensitivity testing for H. pylori infection, certainly not in the United States. So, we're left with treating empirically, making our best guess.

Dr Brian Lacy

Well, I like all that. And also, it's a good reminder for all of us to take a history about prior antibiotic use when considering treatments. So let's consider kind of a hypothetical patient. Let's say I have a patient who lives in the United States, was just diagnosed with a gastric ulcer. He's H. pylori positive, no other warning signs, nothing extravagant. He does not have any known drug allergies or known resistance to antibiotics. What's a good first line therapy for this patient?

Dr William Chey:

Well, really even up until now, I think that a lot of practitioners would say PPI triple therapy, so PPI, clarithromycin, and amoxicillin, hopefully given for at least 10 days and preferably 14 days. But it's important to recognize that the effectiveness of traditional PPI triple therapy, as I just described, is highly influenced by the presence of clarithromycin resistance, by macrolide resistance. We just published the study in the red journal showing that the prevalence of clarithromycin resistance in the United States exceeds 15% in all parts of the United States. In some places as high as 22, 25% of isolates that we identified in a multicenter phase 3 H. pylori treatment trial were resistant to macrolides, to clarithromycin. Remember that in the face of clarithromycin resistance, PPI triple therapy essentially does not work. The eradication rate is less than 40%, probably in the low 30 percentiles.

So what that means from a pragmatic standpoint, in 2017 ACG H. pylori guideline, we said, along with the Maastricht guideline from Europe, that once we get to a macrolide resistance level of 15% or greater, we should no longer be using PPI triple therapy empirically. We haven't completed the updated H. pylori guideline from the American College, but that is what we're going to say in that guideline, I can tell you. So we should be moving away from PPI triple therapy. And you might be asking, "Well, then what should we use?" Well, bismuth quadruple therapy is an excellent choice, so the combination of a PPI, bismuth, metronidazole, and tetracycline is an excellent choice. Also, rifabutin triple therapy, which is another FDA-approved regimen for adults with H. pylori infection, consisting of PPI, rifabutin, and amoxicillin, is an excellent choice.

And finally, there are 2 new regimens that have recently been FDA approved but are not yet available in the United States. Hopefully by the end of 2023, we'll start to see these become commercially available. But they're a combination of a potassium-competitive acid blocker, or P-CAB, with clarithromycin and amoxicillin, so P-CAB triple therapy, or a P-CAB with amoxicillin given 3 times per day, so high-dose dual therapy. And those regimens were both found in a recent US phase 3 randomized-controlled trial to be more effective than traditional PPI triple therapy. So we should be moving away from PPI triple therapy to one of those other regimens that I've just summarized for you.

Dr Brian Lacy

Bill, that's wonderful. You just encapsulated kind of potential first-line therapy. But moving away, more information to come in the American Journal of Gastroenterology. You've talked about second- and third-line therapy. This is just great. And also highlighting the fact that we probably need to think about local antibiotic resistance, especially to clarithromycin, because that would certainly flavor antibiotic choices. So let's think about that patient, whether they went through the first-line therapy or second-line, but especially after first-line therapy, let's say they complete their antibiotics. They're really vigorous about taking it. Do we routinely need to check for eradication? Should we routinely do a breath test or a stool antigen test in all these patients?

Dr William Chey:

Yeah, this is a really important question, and the answer is yes. If you're interested enough to diagnose the infection and to treat, you really have to be interested enough to do a test to prove that the infection has been successfully eradicated. And remember, that can be done with a urea breath test or a fecal antigen test, completed at least four weeks after the completion of antibiotic therapy for H. pylori infection. Or it can be done endoscopically in those infrequent cases where let's say you have a giant gastric ulcer, where you need to do a follow-up endoscopy. You can simply obtain your H. pylori biopsies at the time of that procedure. But it's very important to make sure that you follow through on this confirmatory testing.

And the reason I mentioned that is because, particularly for in-patients, it's easy for those patients to get lost in the shuffle and for them to be discharged without follow-up testing. And remember that in today's day-and-age, where oftentimes, even for GI problems, the follow-up is done by the primary care doctor as opposed to a gastroenterologist, it's really important to just make sure that somebody orders that confirmatory test and make sure that it's been done and checked to be sure that the infection has been successfully eradicated.

Dr Brian Lacy

Well, I just want to highlight 3 things and then clarify the third one. One is, if you thought it important enough to be checking, you should probably be following up after treatment with either a stool test or breath test. Number 1, waiting 4 weeks after therapy, and that's really important, isn't it?

Dr William Chey:

Yes, it is. It's definitely. You do not want to do it before 4 weeks after the completion of the antibiotic therapy.

Dr Brian Lacy

Great. And then kind of by inference, and I'll just have you clarify this, most patients with uncomplicated dyspeptic symptoms, don't need a routine endoscopy for follow-up. They could certainly do a breath test or a stool test. You highlighted the fact that somebody with significant ulcer disease, you're going to be following that person up anyway with an endoscopy, and therefore that's a good opportunity to take biopsies. Is that correct?

Dr William Chey:

Absolutely. Spot on.

Dr Brian Lacy

Okay. So Bill, as we wind down here, you briefly touched on this before, but this is a great opportunity to clarify. What are predictors of success for H. pylori therapy?

Dr William Chey:

Yeah, the biggest predictor is compliance with the regimen. And compliance with the regimen is highly dependent on the patient understanding completely how often to take the medications, for how long, and then lastly, but perhaps most importantly, what the anticipated or possible, I shouldn't say anticipated, but what the possible adverse events might be. A patient that's taking bismuth quadruple therapy is much more likely to continue and complete their therapy, if they know that they may develop some blackening of the tongue or darkening of the stool than if they don't. Otherwise, that's a scary thing. Can you imagine when you look in the mirror and your tongue has turned black or your stool has turned black? A lot of patients know darn well, especially patients that have had a peptic ulcer, that black stool means you're bleeding. Well, it does if you're not taking bismuth. But if you're taking bismuth, it means you're taking bismuth. So making sure that you not only review how often and how long, but also what might happen, will really increase the likelihood that the patient follows through on completing their regimen

Dr Brian Lacy

Patient expectations, it's always important to set that stage and let them know about potential issues. Bill, this has been an absolutely wonderful conversation. Any last thoughts for our listeners?

Dr William Chey:

No, it's an exciting time in H. pylori infection. The reason I say that is because... One thing we didn't talk about is the potential role of antimicrobial-sensitivity testing. And it's important for listeners to realize that we're moving away from traditional culture and sensitivity, which is cumbersome, expensive, and not widely available. And what's coming down the pipe, pretty rapidly right now, is molecular testing, and not just molecular testing of tissue, i.e. gastric biopsies, but potentially molecular testing of stool. Think about how that might be a game changer, if you could order a stool test that would give you critical antimicrobial-sensitivity data. It turns out that stool-based antimicrobial-sensitivity testing using molecular techniques is highly accurate for macrolides and quinolones, which are the two antibiotics that we care about the most, in terms of understanding resistance patterns. So that could be a game changer. It's scalable. The price will come down over time. Stay tuned, because if all of those things happen, it may well be that we'll start to think about using stool-based antimicrobial-sensitivity testing on the front end—hat is before we choose our first course of therapy—as opposed to using that type of testing right now after patients have failed multiple courses of antibiotic therapy.

Dr Brian Lacy

Wow, that's really exciting. And that's what makes medicine so exciting, right? There are these technological changes that should keep us all really interested in this important field. So thank you, Bill. As always, I've learned an awful lot. I know our listeners have learned an awful lot listening to you.

This is Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville. More importantly, for our listeners here today, on whatever service you're using, Apple or Spotify, you've been listening to Dr. William Chey, section chief and professor of medicine in the Division of Gastroenterology and Hepatology at the University of Michigan in Ann Arbor, Michigan, a world's expert on H. pylori, discussing the ins and outs of treating and the reasons why it's important to treat H. pylori. Thank you so much for tuning in today. And we look forward to having you on another podcast in the future.

Dr William Chey:

Thanks, Brian.