H Pylori: rifabutin-based therapy

 There is certainly concern about clarithromycin resistance in the treatment of H pylori. I meant to bring up an article 2 years ago of a study on rifabutin-based therapy, but it unfortunately fell off the list. rifabutin-based treatment seems to be a reasonable alternative for many people (see hylori rifabutin rx AIM2020 in dropbox, or doi:10.7326/M19-3734)

 

Details:

-- 455 treatment-naïve adults with epigastric discomfort and confirmed H. pylori infection, in 55 clinical research sites in the US, in the RHB-105 study (renamed ERADICATE Hp2)

    -- all had dyspepsia for at least two weeks, H. pylori confirmed by ¹³C urea breath test plus upper endoscopy with a positive culture, histology, or rapid urease test, prior to randomization

-- mean age 47 with 93% <65 years old, 62% female, 77% white/19% Black, 60% Latinx.

-- cytochrome P450 2C19 status: 20% rapid metabolizers, 50% normal metabolizers, 21% intermediate, 2% poor metabolizers (see below for significance)

-- exclusion criteria: prior H. pylori therapy, alarm symptoms (anemia, melena, dysphagia, jaundice, or weight loss), more than two active gastric or duodenal ulcers, and receipt of any antibiotics in the prior four weeks, or a PPI or bismuth containing medication in prior two weeks before screening.

    -- Also, those of Asian descent (Far East, Southeast Asia, Indian subcontinent) were excluded because of lower rates of omeprazole metabolism due to polymorphisms in cytochrome P450 2C19 in these populations

-- interventions: 14 days of amoxicillin 3 g, omeprazole 120 mg, and rifabutin 150 mg (divided into q8H dosing), versus an active comparator of amoxicillin 3 g and omeprazole 120 mg (also divided into q8H dosing)

-- Main measurement: ¹³C urea breath tests 4 weeks after treatment

 

Results:

-- there were measurable study drug levels at day 13 in 207 patients (91%) in the rifabutin group and 184 (81%) in the active comparator group; culture and susceptibility results were available for 75% of the participants

-- baseline resistance patterns:

    -- amoxicillin: 22 patients (6%)

    -- clarithromycin: 60 patients (17%)

    -- metronidazole: 150 patients (44%)

    -- both clarithromycin and metronidazole: 36 patients (11%)

-- H pylori eradication rate, per intention-to-treat analysis:

    -- rifabutin group: 83.8% (78.4%-88.0%)

    -- active comparator: 57.7% (51.2%-64.0%)

        -- treatment difference: 26.1 percentage points (18.0%-34.1%), p<0.001

-- H pylori eradication by baseline antibiotic resistance: overall 81.2% (69 of 85 people) on rifabutin versus 56.1% (55 with 98 people) on the active comparator therapy, p<0.001

    -- there was overall no statistically significant difference by the type of resistance at baseline, though most of these comparisons involved very few patients

-- no patient developed rifabutin resistance

-- safety issues: similar numbers of adverse events in both groups, the most common ones comparing rifabutin to active comparator: diarrhea (10.1% vs 7.9%), headache (7.5% vs 7.0%), and nausea (4.8% vs 5.3%); one case of serious adverse event in the rifabutin group (diabetic ketoacidosis) and one in active comparator group (encephalopathy from benzodiazepine overdose)

 

Commentary:

-- there has been uniformity in consensus recommendations regarding the importance of antibiotic treatment for those with either symptomatic or asymptomatic H. pylori infections (eg see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913173/ , or doi:10.1038/ajg.2016.563 )

    -- though in general, the recommended empirical therapies in the guidelines have either been bismuth quadruple (bismuth, metronidazole, tetracycline, PPI) or concomitant triple therapies (PPI, amoxicillin, and  clarithromycin or metronidazole); unfortunately, the first therapy is complex and involves QID dosing, and the latter involves two medications which may well have H. pylori resistance (clarithromycin and metronidazole, as found above)

-- rifabutin is a reasonable antibiotic for H. pylori given that it is bactericidal, it achieves high intracellular and intra-gastric concentrations, and resistance is rare unless it is administered at high doses for long periods of time. And pilot studies have indicated likely effectiveness

-- another study found rifabutin 150mg bid, amoxacillin 1 g bid, and esomeprazole 40mg bid for 10 days led to an 80% cure rate in 39 patients with both clarithromycin and levofloxacin resistance (see https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-020-01370-4) 

-- and a rifabutin meta-analysis in 3052 patients (intention-to-treat analysis) found 73% H Pylori eradication rate, with respective cure rates for second-, third- fourth- and fifth-line therapies of 79%, 69%, 69%, and 72% (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823349/#:~:text=lower%20(0.07%25).-,Mean%20H.,effective%20than%20150%20mg%2Fday. ) this study combined many small studies using different rifabutin treatment regimens, though it seemed that using 300mg/d for 10-12 days seemed best, and all of the regimens used twice a day meds (eg rifabutin 150mg bid, amoxacillin 1g bid, and omeprazole 20mg bid). fyi, there is a single combo pill, Talicia, which combines omeprazole 10mg, amoxacillin 250mg, and rifabutin 12.5mg, to take 4 pills every 8 hours for 14 days (same total doses and same q8h schedule as in the above rifabutin study, though not sure it is actually easier and am sure it is more expensive than individual prescriptions....)

 

-- for a review of the argument to test and treat for H. pylori infections (even asymptomatic ones) see

http://gmodestmedblogs.blogspot.com/2022/03/carcinogen-update-now-including-h-pylori.html , which notes that H. pylori is now considered a carcinogen by the NIH

 

-- there are many reasons that we should have non-clarithromycin-based therapies:

    -- clarithromycin has many adverse effects which make it intolerable to many patients, in particular the GI toxicity

    -- there is no systematic testing of resistance patterns for H pylori in the US to know if the patient is clarithromycin-resistant, or even if resistance is commonly found in certain geographical areas (the assumption being that there might be lots of differences in precsribing in different areas, related to the baseline use of metronidazole and clarithromycin/azithromycin as single agents in the communities for other conditions (eg bacterial vaginosis for the former or respiratory tract infections for the latter prescribed any macrolide including azithromycin)

        -- the best guess overall is that about 30% of people have clarithromycin-resistant H Pylori nationally; this study above found it to be about 17%

    -- overall, the standard clarithromycin-based therapies have had decreasing effectiveness over time (though many of these treatments also include metronidazole which has also had increased H. pylori resistance)

    -- it also seems that effectiveness of antibiotic regimens for H. pylori is best for the initial therapy over subsequent therapies for persistent infection (ie, perhaps best to start with a non-clarithromycin one). though i think the data on this is not so solid (see above-cited study)

--BUT, 14 day sequential therapy, which involves one week of amoxicillin-based therapy, followed by one week of clarithromycin-based therapy, still has high effectiveness:  this is likely related to the fact that clarithromycin resistance is caused by the development of efflux channels that remove clarithromycin from the bacterial cytoplasm, and amoxicillin changes the structure of the cell membrane to prevent effective clarithromycin efflux and therefore clarithromycin ineffectiveness (see http://gmodestmedblogs.blogspot.com/2016/10/h-pylori-regimens-stratified-by.html , which notes high effectiveness of this sequential regimen, and includes a study finding that 89% of patients with documented clarithromycin resistance responded to this sequential therapy, versus 29% on standard therapy: see  hpylori rx sequential annals 2007 in dropbox, or Ann Intern Med 2007; 146:555-563

-- it should be noted that this sequential therapy is more complex and requires more intensive patient education. I personally have found it to be extraordinarily successful, but I do arrange specific nursing appointments to review the details of the therapy as well as filling medication boxes with the appropriate mix of medications. it would be useful to have a comparison study of sequential clarithromycin-based therapy vs rifabutin-based one

-- still, it is a welcome option to have a non-clarithromycin, non-metronidazole-based therapy that seems to work, as in this case with rifabutin. And some of the other antibiotic regimens use levofloxacin, which is also having increasing amounts of H. pylori resistance. 

-- one concern with rifabutin is drug-drug interactions, so would be important to ensure that these either do not exist or medication changes can be made for the 14-day course of therapy to minimize them

-- there is also a recently FDA approved option (as of May 2022) using the dual therapy of vonoprazan 20mg plus amoxicillin 750 mg, both BID for 7 days, in a Japanese study (see H pylori vonoprazan dual therapy 7 days works Gut2020 in dropbox, or https://gut.bmj.com/content/gutjnl/69/6/1019.full.pdf). the former is a novel potassium-competitive acid blocker with stronger and longer-lasting effects on gastric acid suppression than PPIs. this dual therapy was as good as the same plus clarithromycin, with 85% H pylori eradication rate. [i would wait for larger studies in other areas of the world before trying this, which i assume will also be remarkably expensive]

Limitations:

-- this study was limited to patients with symptomatic H. pylori infection. It is reasonable to assume that similar results would be found for asymptomatic patients, but this was not tested

-- the study did not involve people who had been on prior H. pylori treatment regimens, and prior analyses have suggested that the first therapy is the most likely to succeed. So we cannot feel certain that this therapy would work as well in those who had failed prior therapies. one study cited above did find some small fall-off in response moving to the fifth-line therapy, but this was an intention-to-treat analysis, and people needing so many therapies may be different from earlier responders (eg, not take the meds exactly as prescribed). so not really sure that this therapy would be less effective as a salvage regimen

-- this study specifically excluded those of Asian descent because of the frequency of polymorphisms in CYP 2C19 that might affect omeprazole levels, though it was notable that they found no difference in outcomes related to these polymorphisms in non-Asians in this study. The number of people with CYP 2C19 mutations in some of the groups was small, so it is hard to draw clear conclusions; it seems that rifabutin warrants a trial in this group of patients

-- even though we do not have routine antibiotic sensitivity analyses for H. pylori in the United States, the study at least had 55 different clinical research sites in the United States, likely representing an array of H. pylori resistance patterns. there is still a leap going from this type of study with known resistance patterns to one where there are very likely an array resistance patterns in different communities (and it would be great just to have an annual sampling of 100 or so H pylori cultures in different communities to have some idea about likely local resistance). Unfortunately, there is also increasing resistance to levofloxacin, which can also be an effective therapy

So, another real option for many people who are intolerant of clarithromycin and/or metronidazole. This rifabutin-based therapy has not bubbled up to being considered a primary therapy for H. pylori in the guidelines, which all predate this trial, though the data from the study were quite impressive. And, it seems that this would very likely be a useful therapy in those who fail the standard initial therapy. If using this therapy, it is important to assess the potential rifabutin interactions with other medications. and the newer one with vonoprazan might be useful as an alternative (but best to try after more studies are available...)

geoff

 

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