response to the new LTBI treatment guidelines

John Bernardo MD sent me the following, in response to my blog this week on CDC guidelines for LTBI treatment. John is a local expert on TB as a well-regarded national one (has been on some CDC study groups regarding LTBI detection/treatment), and is a great clinician (and person). His reference to 3HP is to the weekly inh/rifapentine therapy for 3 months (see http://gmodestmedblogs.blogspot.com/2018/07/updated-ltbi-treatment-with-weekly-meds.html for my first blog on 3HP, as well as the mmwr on it, which has the references john alludes to).  And, he did give me permission to share this, along with its source…  geoff

I would be a bit careful with the 3HP regimen.

-          It really has been studied only in recently infected people – most over 16 y/o – early in the infection process.  So extrapolating effectiveness, especially by “noninferiority” to 9 mos INH, to all populations with LTBI may be a stretch.

-          Side effect of hypotension, near syncope, syncope is a rare but real problem with this regimen. The CDC paper (Belknap) that supports self administered treatment really showed that SAT WAS inferior to DOT for completion of treatment, but they chose to single out the US study sites only, and they also used “noninferiority” analysis. And it was not powered for safety.  

The CDC 3HP trial, BTW, was not designed originally as a noninferiority analysis – it was changed from a more stringent design a few years into the study. Went through IRB and everything to make the change. It is acknowledged in the NEJM 2011 paper.

And I have to say, those syncope events were scary. One study site dropped out of the CDC’s trial consortium entirely because they were seeing an unusual number of hypotension/syncopes. We never figured out the cause, CDC even commissioned a subgroup to investigate a poss immune mechanism but came up with nothing. I believe the INH + Rpt is a HeRG channel inhibitor – did some expts with a fluorescence model of HeRG in the lab but I think my result may be an artefact, Need to do it with patch clamping – which I don’t have access to !   

And as the study moved along, we realized that the syncopal episodes never happened on the 1^st dose, more often after dose 3 or 4, I believe, were preceded by a prodromal warning on the previous dose. DOT workers were told to hold the next dose if when asked, the subject reported sx like nausea, light headedness, etc … and the number of syncopes dropped off.

As for missed doses, there is no literature regarding effectiveness. For the 3HP study we required completion of the 3 mos HP in 16 weeks; 9 mos INH in 52 weeks.

AND I think we treat too many people for LTBI. We need a test that will tell us not who is infected (for which our current tests are not good at, to start),  but who will develop disease. You know when you and I started taking care of TB patients 40 years ago we didn’t know what caused AIDS. Now we can “cure” it. Other than some minor advances in diagnostics, we still are taking care of TB patients today the same way we did then.

Just a couple of comments:

--it is certainly unfortunate that we do not have a real tool to risk stratify those with positive TB test into those who have very high vs very low risk of developing active TB (and, I would imagine, some of this has to do with the comorbidities they develop later during their lives that might adversely affect their immune system and affect TB reactivation), but I do think that with the current lack of such risk-based knowledge, we should really be testing for LTBI in high-risk young people as much as possible (including those coming from high-prevalence TB countries, which is a large % of the world) and treating them.

--and this is especially true for using rifampin, where there are important drug-drug interactions that make it harder to use in older people on lots of meds

-- the kind of knowledge/experience john noted above really does steer me to using the 4 month rifampin therapy.

--and, I cannot help but add the other side:  the effect of these meds on the microbiome.  All I could find was:

    --those on 4 drugs to treat TB have a profound, long-lasting effect on the GI microbiome (at least 1.2 years), see https://www.nature.com/articles/s41598-017-10346-6  and https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0286-2

        --I could find no studies on the specific risk of rifampin on the microbiome (though I suspect that the more immediately toxic INH has less of an effect on the microbiome than the pretty broad-spectrum rifampin)

    --and an intriguing article suggesting that gut dysbiosis may predispose  to TB disease progression, see https://link.springer.com/article/10.1007/s00018-019-03370-4

Thanks, john

geoff​

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

For access to the dropbox, go to link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

Then go to "clinic", then to either "clinical stuff" for articles, or "powerpt presentations" for the powerpoint presentations

to get access to all of the blogs:

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

3. or you can just click on the magnifying glass on top right, then  type in a name in the search box and get all the blogs with that name in them

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list