Latent TB infection screening: USPSTF guidelines, analysis of treatment regimes

 the US Preventive Service Task Force just published their recommendations for screening people for latent TB infection (LTBI):  see ltbi uspstf2023 in dropbox, or doi:10.1001/jama.2023.4899. For the full evidence backing up these recommendations, see ltbi uspstf2023 evidence JAMA2023 in dropbox, or doi:10.1001/jama.2023.3954

 

    -- screen asymptomatic adults at increased risk of LTBI: grade B recommendation, “moderate certainty that there is moderate net benefit in preventing progression to active tuberculosis by screening for LTBI in persons at increased risk for tuberculosis infection”. The goal here was to screen people in order to treat them, in order to prevent active TB disease and its associated  morbidity and mortality

        -- testing: there is adequate evidence that both tuberculin skin test (ie PPD) and IGRA blood tests are accurate (moderately sensitive and highly specific)

        -- there no good studies that evaluated benefits of screening, but adequate-to-convincing evidence that the treatment works by decreasing progression to active tuberculosis and to a substantial health benefit

        -- there is no direct evidence of harms of screening. the harms of CDC-recommended treatment regimens were small, with the primary harm being hepatotoxicity:

            -- the relative risks of INH hepatotoxicity vs placebo are:

                -- 3.45 (1.49-7.99) for 12 weeks of treatment (24 vs 7 events), mortality rates: 0.03%

                --  4.59 (2.03-10.39) for 24 weeks of treatment (32 vs 7 events) mortality rates: 0.00%

                -- 6.21 (2.79-13.79) for 52 weeks of treatment (43 vs 7 events); mortality rates: 0.01

            -- the relative risk of INH hepatotoxicity for INH are 4-fold higher than rifampin: RR 4.22 (2.21-8.06)

            -- the RR for INH vs INH-rifapentine: 0.43% vs 2.70, 84% decrease for INH-rifapentine, RR 0.16 (0.10-0.28)

-- they specifically cite the importance of routine screening of those in correctional facilities and those who are homeless, who are at significantly higher risk of TB disease (11-fold in homeless persons)

-- there is insufficient evidence for the USPSTF to make specific recommendations around individuals with diabetes

-- no evidence to make recommendations about the optimal frequency of screening, noting that screening frequency could be one-time only in those that low risk for future TB exposure, up to annual screening among those at continued risk of exposure

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Treatment for patients with LTBI should be individualized (per the CDC recommendations):

-- those with a clear indication for treatment include:

    -- people who are at increased risk because of a recent TB exposure, such as close contacts with persons having untreated TB, healthcare workers or others working in high-risk congregate settings who thereby may have occupational TB exposure

    -- individuals with a high risk of reactivation who have LTBI: specifically those who are immunocompromised

    -- individuals at moderate or slightly increased risk of reactivation, specifically those who reside in an area where TB is prevalent

        -- high risk of reactivation:  those who have HIV, transplants, silicosis, chronic kidney disease (the American Thoracic Society/Infectious Diseases Sociay of America and the CDC (see https://www.cdc.gov/tb/publications/guidelines/pdf/ciw778.pdf ) do not specify what level of CKD matters), TB infection within the past two years, abnormal chest x-ray (not granulomas, but apical fibronodular changes consistent with TB), head and neck cancer, or taking TNF-α  inhibitors

            -- moderate risk: on steroids, diabetes, younger than 4 when infected

         -- areas of high risk (for patients who come from countries in the Boston area, see report for details in other areas): Cape Verde, Haiti, Vietnam, many countries in Africa, Brazil, Peru.

    -- the CDC itself, but not the full USPSTF document above, also considers as elevated risk: people who had gastrectomy/jejunoileal bypass, those with low BMI, and those with substance use disorder

    -- also, individualized testing should be considered, per a conversation between the clinician and patient

 

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A recent article performed a network meta-analysis of different regimens for treating latent TB infections: see ltbi rifamp vs rifabut rx LancetResp2023 in dropbox, or doi.org/10.1016/ S2213-2600(23)00096-6 

 

Details:

-- a network meta-analysis is used when there are no head-to-head comparisons of the relevant interventions. This type of analysis involves assessing the relative merit of different medications as compared to a third medication (including placebo), mathematically attempting to adjust for population differences, and then determining the relative potency of those medications as if they were compared to each other

-- in this case, tuberculosis preventative regimens based on rifampin and rifapentine were compared, based on studies comparing these meds individually to INH

-- all RCTs compared LTBI regimens: either 3HP (4897 patients) or 4R (4055 patients), compared to 6H or 9H (total of 8620 patients)

    -- 3HP: weekly rifapentin 900mg plus INH 900mg for 3 months (a total of 9 pills at a time, once a week for 12 weeks)

    -- 4R: daily rifampin 600 mg/d

    -- 6H: 6 months of INH 300 mg/d

    -- 9H: 9 months of INH 300 mg/d

-- 96% overall had LTBI assessed by tuberculin skin test, IGRA was performed in about 7%; 84% had normal baseline chest x-ray, abnormals were often not related to tuberculosis

 -- individual-level patient data were accessible in all studies

 

-- 17,572 participants from 14 countries in 6 trials

-- mean age 35, 51% female, BMI 25

    -- age, sex, BMI, and recreational drug use were similar across treatment groups

-- treatment indications:

    -- close contacts in 83% (69% were close contacts with at least 4 hours per week of contact with a confirmed active TB case), though more close contacts were on the 4R regimen

    -- recent converters: 16%, though very few in the 4R group

    -- HIV in 7% (range from 0 to 100%, higher in studies of 3HP (10% vs 3%), though antiretroviral therapy use was higher in the 4R group (49% vs 1%)

    -- alcohol use: current/ever: 3%/23% (the latter more in the 3HP group)

    -- very few were on biologic agents (eg TNF-α), immunosuppressants; or had diabetes, or renal failure, or used recreational drugs 

 

Main outcomes:

-- treatment completion rates

-- adverse events

-- incidence of subsequent tuberculosis disease

 

Results:

-- treatment completion rates:

    -- 3HP: 3963 of the 4897 patients (81%) vs 2856 of 4614 (62%) receiving one of the INH dosages

    -- 4R: 2828 of 3865 patients (73%) vs 2270 of 3823 patients (59%) on 9H (all in the relevant study were on this 9 month dose)

    -- 3HP vs 4R (by network meta-analysis): adjusted relative risk (aRR) 1.06 (1.02-1.10), adjusted risk difference (aRD) 0.05 (0.02-0.07) [ie 5%  better for 3HP]

-- treatment-related adverse events leading to drug discontinuation:

    -- adverse events of any severity, 3HP vs 4R: aRR 2.86 (2.12-4.21), aRD 0.03 (0.02-0.05) [ie 3% worse for 3HP]

    -- grades 3 to 4 adverse events: aRR 3.46 (2.09-6.17), aRD 0.02 (0.01-0.03) [ie 2% worse for 3HP]

-- incidence of subsequent active TB, rates per 1000 person-years:

    -- 3HP vs 6-9H: 3 cases vs 4, nonsignificant

    -- 4R vs 9H only: 1 in each group, nonsignificant

    -- 3HP vs 4R: nonsignificant difference

 

Sensitivity analyses:

-- patients stratified by age:

    -- <18yo: higher completion rate of 3HP than the entire study population, aRR 1.12 (1.01-1.23), and aRD 0.07 (0.00-0.15)

    -- <35yo: had similar completion rates to those <18yo

    -- >35yo: similar completion rates to the entire population as above

        -- 35-65 yo and >65yo: no difference from the entire population

-- patients living with HIV (1271 people):

    -- treatment completion rate: substantially higher for those receiving 3HP versus 4R

        -- no HIV (11,817): results were similar to the overall population, as above

-- adverse events leading to permanent drug discontinuation: slightly higher with 3HP than 6-9H

    -- comparing 3HP vs 4R: aRR 2.86 (2.12-4.21), and aRD of 0.03 (0.02-0.05)  [3% worse for 3HP]

    -- fewer adverse events overall in those with HIV

 

Commentary:

-- the global burden of tuberculosis is quite high, with an estimated one quarter the world’s population living with tuberculosis infection (ie, LTBI); in 2021 there were 10.6 million reported cases and 1.6 million deaths from TB disease (ie, progressing to active TB)

-- those with LTBI have a 5 to 10% risk of developing tuberculosis disease (though this risk is considerably higher in the first two years following infection)

-- in the US, there is still a 10% mortality in people who are diagnosed with active tuberculosis

-- the main historical treatment for tuberculosis has been INH, for either 6 or 9 months (used to be 12 months for some, such as those with HIV). The issue with INH is the length of therapy (leading to relatively low numbers who complete the therapy) as well as potentially fatal hepatotoxicity. Hence the advantage of these shorter courses having less hepatotoxicity

    -- it is notable above, as well as in other studies, that the 3HP group with 900 mg of INH (but only once a week) had very low rates of hepatotoxicity

    -- another issue is the neuropathy associated with INH. Any persons with inadequate diet or history of neuropathy or at high risk of developing neuropathy (including those with diabetes, uremia, alcoholism, malnutrition, seizure disorder) should be supplemented with pyridoxine (vitamin B6) 50mg/d to prevent or treat peripheral neuropathy.

-- a significant number of immigrant patients that I see do come from a high risk TB countries. Even though they are living in the US, a pretty low risk country, I think that LTBI should be tested for and treated for a few reasons:

    -- 70% of cases of tuberculosis disease in the United States are from individuals who are born or lived mostly in countries with a high prevalence of tuberculosis

    -- many patients do go back and forth to their high risk countries, sometimes staying many months (ie, consider retesting on return from their countries)

    -- the toxicity of treatments as well as the difficulty of treatments tends to get more complicated as people get older.

        -- older people may well be taking more medications, and the rifamycins have a myriad of drug-drug interactions (though rifampin and rifabutin are metabolized differently and have somewhat different drug-drug interactions)

        -- hepatotoxicity of INH happens more often in older people (so, better to find and treat when they are younger)

        -- and with aging, there tends to be both accumulated comorbidities as well as a less robust immune system: both of these might predispose them to a higher chance of reactivation TB (for the many changes in one’s immune system with aging, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291468/)

 

-- the above network meta-analysis found that there did not appear to be much difference between these two therapies: 3HP had a 5% increased completion rate at the cost of a 2 to 3% increase in adverse events, and neither had any significant increase in subsequent development of tuberculosis disease

-- it was notable that in people living with HIV, the rate of adverse events was actually lower as well as the subsequent development of active tuberculosis

-- one advantage of this study was the availability of individual patient-level data, especially with the large numbers of patients involved, does add to the rigor of the analysis

  

Limitations:

-- though a network meta-analysis was necessary to get a sense of the relative potency of the 3HP and 4R regimens (given the lack of studies directly comparing these 2 regimens), this type of analysis does not have nearly the statistical power of direct comparison by RCTs

    -- the studies were done in different countries with different healthcare systems, as well as differences in access to care, tuberculosis rates, possibly different TB resistance patterns, and with different chosen treatment strategies (3HP or 4R versus INH; and perhaps the different treatments were chosen by their clinicians for specific undocumented reasons??). all of these factors might undercut the generalizability of their results to other populations

-- not a lot of kids to make robust assessments, though there were few adverse events and the high completion rates in those under 18 years old, suggesting at least that the regimens were tolerable

-- this article was lacking in a few very important details (including in the article supplement):

    -- there was no table of the specific adverse effects, only global categorizations; also no documentation about the severity of the different complication.

    -- there were remarkably low numbers of patients who developed active tuberculosis in this study. But there was no comment on over what time period this was assessed.  reactivation TB tends to happen more often soon after a new tuberculosis infection, in young children, and especially in older people. It was noted that the preponderance of patients in these studies were from close contact or recent converters. but we do not know if they assessed people 6 months later, 10 years later, etc, or if the close contacts were later evaluated for having actually gotten the TB infection (though being in a close place >4 hours per week seems to be a good marker of actual infection risk). so i am not sure what to make of their data on the progression from infection (LTBI) to TB disease. Or how relevant it is to the vast majority of our patients in the US who have positive TB tests likely from TB infections in the distant past.

-- the assessment of treatment completion rates was self-reported, except those who were under DOT (directly-observed therapy), and liable to bias

    -- there were very limited objective data (ie, those on DOT): only done in one trial of 3HP vs 9H and none on 4R

-- although they did have information on patients who were recent converters, used biologic agents, had immune suppression, had HIV, smoked or used alcohol, there were very few people who had most of the other higher risk conditions, thereby limiting the generalizability to many patients

-- all treatment arms were unblinded in the included trials, which would could introduce bias.

 

So, though this study does have significant weaknesses, as noted above, it does raise several important issues:

-- we are clearly underscreening people who have moderate to high risk for subsequent TB reactivation later in life. Many would likely benefit from LTBI treatment (testing really makes sense in those who would be interested in treatment)

-- there are much shorter and safer regimens than INH available now (though INH is an important treatment in those where a rifamycin-based treatment is not appropriate, such as those with drug-drug interactions with important meds they need for other medical conditions)

-- primary care is the ideal setting for patient assessment, screening, and treating LTBI. We in primary care usually have the best holistic sense of the patients as well as (perhaps) the resources to help improve medication adherence more than a TB clinic

    -- BUT, the big issue, of course, is that this is just one more task on the already overflowing plate of issues that primary care clinicians need to deal with: see http://gmodestmedblogs.blogspot.com/2023/04/healthcare-worker-burnout-whither.html.

        -- the very short time we have to see a patient in primary care (about 15-20 minutes or so) really does make it hard to focus on perhaps the very long-term risk of developing active TB at the expense of dealing with the current multitude of medical and psychosocial problems in patients…..

        -- this all reinforces, yet again, the need for fundamental restructuring of our healthcare system in ways that make primary care actually doable.

-- perhaps this task of screening and treating LTBI may be more implementable in a community setting, with the active participation of community health workers, medical assistants, nurses, social workers, etc., when these are available. (those of us working in community health centers may have a real advantage here….)

 

geoff

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