Updated LTBI treatment with weekly meds

The CDC updated their treatment recommendations for latent tuberculosis infections (LTBI), specifically regarding the three-month course of weekly rifapentine plus isoniazid (see tb once weekly rx mmwr2018 in dropbox, or https://www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6725a5-H.pdf ).

Details:

-- the CDC had supported the use of directly-observed therapy (DOT) with once weekly rifapentine and isoniazid for a total of 12 weeks as an effective option for LTBI in 2011, though excluded those <12 years old, or those with HIV infection

-- in 2017, 19 articles representing 15 unique studies were included in a meta-analysis to extend these guidelines. The majority of these studies were considered to be of good quality.

-- no eligible studies included patients <2 years old

--Dosages:

    -- isoniazid (orally once weekly for 3 months): 15 mg/kg, rounded up to the nearest 50 or 100 mg; 900 mg maximum (typical adult dose)

    -- rifapentine (orally once weekly for 3 months):

        -- 10 to 14 kg: 300 mg

        -- 14.1 to 25.0 kg: 450 mg

        -- 25.1 to 32.0 kg: 600 mg

        -- 32.1 to 49.9 kg: 750 mg

        -- ≥50 kg: 900 mg maximum (typical adult dose)

Results:

-- the CDC continues to recommend this three-month treatment for adults, referred to as 3HP, with new additions:

    --people age 2 to 17 yo

        --3HP was well-tolerated and as effective as 9 months of daily isoniazid for preventing TB and had higher treatment completion rates

        -- several health departments have already been using 3HP in kids as young as 2 years old with high treatment completion rates

    -- people with HIV infection and on antiretroviral medications compatible with rifapentine

        -- new studies show the effectiveness of 3HP in both those with HIV on or not on antiretroviral therapy, and there is not a clinically significant drug interaction between once weekly rifapentine and either efavirenz or raltegravir

    -- it is acceptable to use either DOT or self-administered therapy (SAT) in those >2 years old

        -- an RCT found that SAT was noninferior to DOT in persons over 18 years old, particularly in the US (see tb weekly rx LTBI annals2017 in dropbox, or Belknap R. Ann Intern Med. 2017;167:689-697. doi:10.7326/M17-115) 

Commentary:

-- who to test for TB: 

    --individuals at risk for new TB infection (contacts with patients who have active TB, illicit drug users, residents/employees in homeless shelters or correctional facilities, health care workers/other occupations with risk of exposure to untreated patients with active TB

    --those at increased risk of TB reactivation:

        --high risk (test all): HIV, transplant/chemotherapy/immunocompromise, lymphoma/leukemia/head and neck cancer, apical fibronodular changes on CXR consistent with healed TB (not just granulomas), silicosis, renal failure on dialysis, treatment with TNF-a inhibitors

        ​--moderate risk (test all if in groups with increased LTBI prevalence): diabetes, systemic steroids >15 mg/d for>1 month

        --slight increased risk (test if increased prevalence of LTBI): underweight (eg BMI<20), cigarette smoker >1ppd, CXR with solitary granuloma, those from counrtries with high prevalence of TB

            ​-- for most current list of countries with high burden of tuberculosis (this ranking does change annually), see http://www.stoptb.org/countries/tbdata.asp 

-- per the CDC,  in 2014, 66% of TB cases in the US were from foreign-born individuals, most from Mexico, Philippines, Vietnam, India, China, Haiti and Guatemala (though Guatemala is not on the high burden list….)

-- 2 of the most prevalent ethnicities at our health center (Cape Verdean and Dominican) bring up some more general issues:

    --Cape Verde: the incidence of TB in 2006 was about 153 cases/100K people, decreasing to 137/100K in 2016 (see https://tradingeconomics.com/cape-verde/incidence-of-tuberculosis-per-100-000-people-wb-data.html ). BUT, there is a significant issue of underreporting of TB. For example, there was a 40% underreporting in Praia (capital of Cape Verde) from 2006-2012. my guess is that there is a large overlap between those countries with high rates of TB and those that have less complete epidemiological data

    --Dominican Republic: about the highest rate of TB in the Americas, at 91 cases/100K people. They have had an aggressive directly-observed therapy program, detecting and treating 80% of the population (which is pretty remarkable), with current programs to manage Multi-Drug Resistant TB (the Domican Republic being a world “hotspot” for MDR, see http://www.who.int/bulletin/volumes/85/5/06-036459/en/ )

--further CDC recommendations:

    -- all patients should be evaluated for active TB prior to any LTBI regimen

    -- all patients should be advised of possible adverse effects of the meds, including drug hypersensitivity reactions, rash, hypotension, or thrombocytopenia

    -- there should be monthly evaluations to assess treatment adherence and adverse effects

    -- there should be baseline hepatic chemistry blood tests (at least AST levels) for patients with: HIV, lipid disorders, less than 3 months postpartum, regular alcohol use, injection drug use, or use of TB meds with known drug interactions

    -- repeat blood tests in those with baseline liver abnormalities or others at risk for liver disease. Discontinue 3HP if serum AST level is >5 times upper limit of normal in the absence of symptoms or >3 times ULN in those with symptoms

    ​-- discontinue 3HP in the presence of severe reactions; conservative management and continuation of 3HP can be considered in those with mild to moderate adverse events

-- some of the experts in the above panel still preferred DOT for children aged 2 to 5, since the risk of TB progression and severe disease is higher than in older children or adults

-- adverse events: 4% of all patients on 3HP experience flulike or other systemic drug reactions with fever, headache, dizziness, nausea, myalgias, bone pain, rash, itching, red eyes, or other symptoms. 5% discontinue 3HP because of adverse events, typically after the 1^st 3 to 4 doses. Symptoms usually resolve without treatment within 24 hours

    -- see https://www.cdc.gov/tb/publications/pamphlets/12-doseregimen.htm for a symptom checklist for patients and staff

-- rifapentine can interact with other medications (e.g. methadone or warfarin), and may reduce the effectiveness of hormonal contraceptives

-- in terms of HIV meds, best to check https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf , which has a large and frequently updated list of drug-drug interactions (last 10/17/2017)

    -- For PIs (see their table 18a): do not use any with rifampin or rifapentine

    -- For NNRTIs (see their table 18b): only use EFV, with no dose adjustment

    -- For NRTIs: (see table 18c): don’t use TAF with either rifampin or rifapentine (these significantly reduce TAF levels)

    -- For INSTIs: (see table 18d): 

        --rifampin: increase DTG dose to 50mg bid (though do not use in those with DTG mutations); RAL: increase to 800mg BID

        --rifapentine: can use only RAL at dose of 400mg bid

--and, shockingly enough, rifapentine is a really cheap drug

--i checked out the above recommendations about TAF and found on several different websites (drugs.com, and a couple of others) that said not to use rifapentine with TDF as well as TAF. So, to clarify I called the HIV warmline in San Francisco and they confirmed that rifapentine does not have a significant drug interaction with TDF, but does with TAF. The physician in San Francisco stated that the metabolism of the 2 drugs is different and that TDF was fine, and she suggested using the University of Liverpool HIV drug interaction site for better info: https://www.hiv-druginteractions.org/checker​

so, my limited but increasing experience is that this 3 month treatment is great. Minimal problems encountered. my prior go-to regimen was rifampin for 4 months (unless rifampin were contraindicated by drug-drug interactions)​, which is a much shorter course than 6-9 months of INH and much less hepatotoxic. For these rifamycin-based therapies, it seems reasonable to see if the patient prefers a single drug daily for 4 months or the 2 drugs weekly (which has a signficant pill burden: for adults, INH 900 mg means taking 3 pills of 300mg and rifapentine 900mg means taking 6 pills of 150mg; ie 9 pills at once). 

The hardest issue, to me, is for patients with HIV, who are increasingly on regimens containing INSTIs (no longer so much raltegravir, however, since it is BID and more prone to be associated wtih resistance mutations) and increasingly on TAF.  one probably could do dolutegravir 50mg bid along with TDF/FTC, treat the LTBI, then change to a more standard therapy (i have recently been using lots of bictegravir/emtricitabine/TAF, which is a single pill, much cheaper, and pretty resistant to HIV resistance mutations. see http://gmodestmedblogs.blogspot.com/2018/04/hiv-guidelines-new-combo-pill-gets-top.html 

i also fear that we clinicians (myself included) may be currently undertesting patients for LTBI.  A few decades ago it was a routine test done in kids and people coming from higher-risk countries, then the test was down-graded to "as indicated, in moderate to high risk people" and not part of the “routine” mental checklist. this was probably reasonable overall, but i think it made testing much less likely to be done even in those who really should have had it.  also, LTBI is asymptomatic and treatment is to prevent TB reactivation typically much later in life, when the immune system is less able to contain the mycobacteria, either because of age or other factors developing later that impair the immune response (diabetes, cancer...). so, it is often the case that we spend our limited time with patients dealing with current medical/psychosocial problems over an asymptomatic disease which may become a problem in the distant future.

in any event, this expanded recommendation for the once-weekly rifapentine/INH for 12 weeks should make treatment for LTBI  easier, though there should be systems in place to call patients regularly to make sure they are not having adverse effects and that they are taking the meds appropriately. the above symptom checklist ( https://www.cdc.gov/tb/publications/pamphlets/12-doseregimen.htm )  provides a reasonable tracking system, and could be administered by a medical assistant or others.

http://gmodestmedblogs.blogspot.com/2016/09/uspstf-ltbi-screening-recommendations.html reviews the USPSTF recommendations about LTBI screening in high risk populations, testing, and treating recommendations; it includes references to prior blogs about concerns regarding the accuracy and stability of IGRA testing.

geoff​

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