h pylori regimens

BMJ just published a network meta-analysis of h pylori eradication by different regimens (see hpylori rx review bmj2015 in dropbox, or BMJ 2015;351:h4052). They identified 143 studies with 14 different treatments. Some varied by length of treatment, some by antibiotics used, some by addition of probiotics, and some by consistent vs sequential therapy. 

background (as noted in prior blogs):

--H pylori  is associated with an array of GI issues (dyspepsia, PUD, gastric mucosa-associated lymphoid tissue lymphoma or MALT, gastric cancer), as well as Fe-deficiency anemia, ITP, and perhaps due to its systemic inflammatory effects, may be associated with neurologic disorders (alzheimers, parkinsons, stroke) as well as cardiovascular disease

--H pylori is the most common human pathogen, infecting about 50% of the global population (about 30% in North America and northern Europe, higher numbers in Eastern Europe, South America, Asia, Africa).

--the effectiveness of the initial standard therapy (PPI, clarithromycin, and amoxacillin or metronidazole) has decreased over time

--since there are no studies comparing multiple treatment strategies, the use of a network meta-analysis allows us to mathematically compare different regimens, provided that there is a common comparator (which, in this case was 7 days of standard treatment with PPI, clarithro, and amox or metronidazole. 

results:

--32,056 patients were involved in the efficacy analysis and 22,180 in the treatment tolerance analysis

--average age 47, 53% men

--the real laggards in treatment efficacy (documented elimination of h pylori) were:

    --7 days of levofloxacin, PPI, and 1 antibiotic

    ​--7 days of bismuth, PPI and 2 antibiotics

--in general, longer treatments did better, though the top rankings were (with the reference being the 7-day standard treatment, which has eradication rate of 0.73 (0.71-0.75):

    --7 days of PPI, 3 antibiotics (often amox, clarithro, and 5-nitroimidazole) [5-nitroimidazoles include metronidazole and tinidazole, though h pylori sensitivities to these different 5-nitroimidazoles can vary]: eradication rate of 0.94 (0.89-0.98)

    --10 or 14 days of PPI and 3 antibiotics (often amox, clarithro, and 5-nitroimidazole): eradication rate of 0.91 (0.87-0.94)

    --10 or 14 days of PPI, clarithro and (amoxacillin or metronidazole), supplemented by probiotics: eradication rate of 0.90 (0.85-0.94)

    --10 or 14 days of PPI, levofloxacin, plus 1 antibiotic: eradication rate of 0.90 (0.84-0.94)​

    --10 or 14 days (sequential) -- 5 or 7 days of PPI plus amoxacillin, followed by 5 or 7 days of PPI, clarithro and (5-nitroimidazole or amoxacilin): eradication rate of 0.87 (0.85-0.90)

    --10 or 14 days of PPI, bismuth compounds, and 2 antibiotics: eradication rate of 0.85 (0.82-0.89)​​

--tolerance to therapy

    --in general, the shorter the course of therapy, the better tolerated

    --the best tolerated therapies were:

        --7 days of the standard 7 days of PPI, clarithromycin and (amoxacillin or metronidazole) along with a probiotic, having a risk of adverse events being 35% lower than the standard 7 day treatment by itself

        --7 days of PPI, levoflox and 1 antibiotic

        --the rest did not reach statistical significance

so, a few issues:

    --see the array of H pylori articles in prior blogs, including more specific data on some of the more useful regimens (see http://gmodestmedblogs.blogspot.com/search/label/H%20Pylori  )

    --i did not include the network meta-analysis results using rantidine bismuth citrate, since this does not appear to be available in the US

    --this network meta-analysis is a mathematical tool to try to look for relative rankings of different therapies which were never directly compared, and suffers from several issues. one of the most important is that h. pylori antibiotic sensitivities range dramatically from one country to another (likely based on prevalent use of the antibiotics for other indications in that country, leading to h pylori resistance), and there are studies showing improved h pylori eradication with targeted therapies based on resistance patterns 

    --one interesting/paradoxical conclusion from this network meta-analysis is that, as opposed to all other comparisons, the shorter duration of PPI and 3 antibiotics fared better than the 10 or 14 day courses of the same regimen

    --another striking finding was that the bismuth based regimens did somewhat less well, despite a very strong study (see http://gmodestmedblogs.blogspot.com/2015/04/h-pylori-rescue-therapy.html  )

    --as a meta-analysis, it is hard to get more specifics (when they give choices, such as amoxacillin or metronidazole, are there any differences between them. or between the different 5-nitroimidazoles. or it there a difference by which probiotics were used. or is there any difference between 10 and 14 days of therapy.) also, some of what would seem to be the best regimens had very few participants, so the confidence intervals were very large, and they were under-represented in the final analysis. the studies using probiotics were both fewer in number and of poorer design. and, they were unable to control for smoking and alcohol, potential effect modifiers.

    --and, one very important issue in the US is that we do not have data (at least in Boston) on h pylori sensitivities. maybe that makes sense. one of our greatest assets in Boston is the wonderful ethnic diversity here. one of the problems (at least as h pylori is concerned) is that h pylori organisms from different parts of the world are here​ with their different antibiotic sensitivities. so applying averaged sensitivities may not really benefit the individual patient in front of you.

    ​--my best guess, from my own experience and reading, is that i use the 10 day sequential therapy (a bit more complicated: 5 days of PPI bid and amoxacillin 1gm bid, followed by 5 days of PPI bid, clarithromycin 500 bid, and metronidazole 500 bid), and in the very few cases of persistent infection (mostly detected by stool antigen testing), i use the bismuth based regimen: high dose PPI bid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate 240mg bid for 14 days. so far, so good.... but i should add that the standard 7 day treatment does well in areas where there is clarithromycin resistance rates of <10% (as in the UK). but lacking data in the US, where there are lots of (unnecessary) azithromycin prescriptions (eg, see http://gmodestmedblogs.blogspot.com/search/label/antibiotic%20resistance  ), i suspect that h pylori resistance is pretty high.