Version May 2024
INTRODUCTION — Tuberculosis (TB) terminology is inconsistent in the literature and in practice (table 1) [1]. The following terms are used in this discussion (see 'Terminology' below):
●Tuberculosis infection (newer term for latent tuberculosis; "TBI")
●Tuberculosis disease (newer term for active tuberculosis)
The distinction between TB infection and TB disease is important. In most individuals, Mycobacterium tuberculosis infection is either cleared or contained (via innate and acquired immune defense mechanisms). Individuals whose immune system initially contains the organism are asymptomatic and noninfectious, though likely harbor potentially viable organisms [2]. This situation is referred to as TB infection; the older term "latent TB" may be misleading since such individuals are infected with viable mycobacteria in various stages of containment by the host immune system [1].
Containment of TB infection is a dynamic process; organisms have the potential to overcome immune defenses and subsequently cause symptomatic disease. Treatment of TBI prior to development of TB disease kills contained organisms, thereby reducing the risk of developing TB disease (termed reactivation TB) by as much as 90 percent [3]. Treatment of TBI has the potential to protect the health of the infected individual as well as the public by reducing the number of potential future sources of infection to others [4,5].
Treatment of individuals with TB disease is the first priority for TB control; an important second priority is identification and treatment of individuals with TBI, especially those who are at high risk for developing disease [6-9].
Following TBI treatment, the durability of protection against reactivation is variable and depends upon regional prevalence of TB and risk for reexposure. TBI treatment may confer lifelong protection against disease; among Alaskan Native persons, for example, the protective effect of isoniazid prophylaxis has been shown to persist for more than 19 years [10].
The approach to treatment of TBI in patients without human immunodeficiency virus (HIV) will be reviewed here. Treatment of TBI should be initiated only once TB disease has been excluded [11].
Diagnostic testing for TBI is discussed in detail separately. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
Treatment of TBI for patients with HIV or receiving tumor necrosis factor-alpha inhibitors is discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)
Treatment of TBI in pregnancy and in children is discussed in detail separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy" and "Tuberculosis infection (latent tuberculosis) in children".)
TERMINOLOGY — TB terminology is inconsistent in the literature and in practice as discussed above [1]. Relevant terms are defined in the table (table 1). (See 'Introduction' above.)
WHOM TO TREAT — The goal of TBI screening and treatment is to identify individuals who are at increased risk for the development of TB and therefore would benefit from treatment of TBI. Only those who would benefit from treatment should be tested, so a decision to test presupposes a decision to treat if the test is positive (table 2).
The decision to initiate TBI therapy should be made by someone who is familiar with the risks and benefits of TBI therapy, including the advantages and disadvantages of different regimens. TBI treatment should be initiated only for patients in the categories for which treatment confers benefit [6,12,13]. Those who have undergone testing who fall outside these categories should not receive TBI therapy, as risk outweighs potential benefit. For patients initiating long-term immunosuppressive therapy who are anergic or have inconclusive TBI testing, treatment decisions should be based on the presence or absence of epidemiologic risk factors for TBI. Issues related to screening are discussed in detail separately. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Balancing risk of disease and risk of treatment' and "Epidemiology of tuberculosis".)
PRIOR TO TREATMENT
Exclude TB disease — Prior to starting treatment for TB infection, we ensure that there are no signs or symptoms of TB disease based on history (eg, fever, cough, weight loss, night sweats) and physical examination; however, over half of people with TB disease do not have symptoms, so it is also important to obtain a chest radiograph to rule out asymptomatic disease (algorithm 1) [14,15]. This evaluation is important to avoid undertreatment of TB disease, which can lead to emergence of drug resistance [16]. Patients with signs or symptoms suggestive of TB disease warrant further diagnostic evaluation. (See "Diagnosis of pulmonary tuberculosis in adults".)
It can be challenging to distinguish TB infection with old, healed disease from culture-negative TB disease; in both conditions, chest radiography may be consistent with TB, but sputum cultures are negative. In the setting of clinical suspicion for TB disease (based on presence of symptoms and/or radiographic evidence of progression), treatment for culture-negative disease (rather than TBI) should be pursued. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Culture-negative TB'.)
Assess comorbidities — Comorbidities that should be considered in planning treatment of TBI include underlying liver disease, neuropathy, and concomitant medications.
Regimens for treatment of TBI are associated with hepatotoxicity; the risk of hepatotoxicity is greatest with isoniazid and less so for the rifamycin-based regimens. Baseline liver enzyme testing is appropriate for the following nonpregnant adults (table 3) [7]:
●Patients with heavy alcohol use, liver disease, or chronic hepatitis
●Patients currently injecting drugs
●Patients on potentially hepatotoxic medications
●Patients with history of elevated serum transaminase concentrations
Baseline liver enzyme testing may also be considered on an individual basis for other patients but need not be performed routinely. Active hepatitis and end-stage liver disease are relative contraindications to the use of hepatotoxic agents for TBI treatment. For patients with baseline serum transaminase levels greater than three times the upper limit of normal, TBI treatment decisions should be deferred pending evaluation of the underlying cause.
The risks and benefits of initiating treatment of TBI in patients with abnormal baseline liver function (alanine aminotransferase [ALT] >3 times the upper limit of normal) should be considered carefully. Clinical considerations include baseline ALT level, alcohol use, age, presence of viral hepatitis, and the risk of TB progression [17]. If therapy is required, serum transaminases, bilirubin, and international normalized ratio should be monitored every two to four weeks [17].
The potential for drug-drug interactions with rifamycins is high for individuals taking the following drugs: warfarin, oral or other hormonal contraceptives, some antihypertensives, some antiarrhythmics, some antidepressants, some anticonvulsants, methadone, and the protease inhibitor class of antiretroviral drugs. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)
CLINICAL APPROACH
Selecting a regimen — Thus far, none of the available treatment regimens has been shown to be superior to any of the others. Therefore, the choice of regimen is based largely on the likelihood of adherence, the potential for adverse effects, and preference (of the patient, provider, and/or public health program) [6].
Low-incidence settings — For treatment of TBI in adults without HIV infection in low-incidence settings (TB incidence rate <100 per 100,000 population), we are in agreement with the guidelines for treatment of TBI issued by the United States Centers for Disease Control and Prevention (CDC) and National Tuberculosis Controllers Association (NTCA) in 2020, which favor a rifamycin-based regimen over isoniazid monotherapy [6]. Rifamycin-based regimens are generally preferred given their efficacy, favorable treatment completion rates, and relatively low hepatotoxicity rates, despite various important interactions of many drugs with rifamycins.
Given detection of increased levels of nitrosamine impurities in samples of rifampin (RIF) and rifapentine (RPT) announced by the US Food and Drug Administration (FDA) in August 2020 [18,19], isoniazid (INH) monotherapy may be considered as an alternative regimen for adults with newly diagnosed TBI. Nitrosamines are commonly found as contaminants in processed foods and beverages as well as some medications. They also are produced endogenously following ingestion of some foods, drinks, or medications. Some nitrosamines have been implicated as possible human carcinogens based largely on long-term animal studies. The risk of cancer (if any) among individuals who complete a 4-month course of RIF or a 12-dose course of RPT with current levels of contamination by these compounds is unknown. Regulatory agencies worldwide have set upper acceptable intake limits for these compounds [20].
In the United States, to preserve the supply of these important drugs, the FDA increased the upper acceptable daily intake limits for RIF and RPT and is working with manufacturers to reduce nitrosamine levels in these products [19].
Because the risks from TB appear to be greater than those from cancer, and the risks for serious toxicity such as INH-induced hepatitis may be substantial with alternative regimens, the CDC and FDA recommend that these RIF and RPT continue to be used for treatment of TBI and TB disease. This should be done following individual patient discussion of benefits, risks, and alternatives. Some clinicians choose to avoid rifamycins in all but highest-risk individuals (and those with TB disease) and offer INH-based regimens (with known risks for serious toxicity) to lower TB-risk patients; others may defer treatment in lower TB-risk persons until more information is available.
Rifamycin-based regimens include (table 4):
●RIF daily for four months (regimen abbreviation: 4R).
●INH and RIF daily for three months (regimen abbreviation: 3HR).
●INH and RPT weekly for three months (regimen abbreviation: 3HP) – This regimen may be used for otherwise healthy patients age ≥2 years; data to support its use are based on four high-risk groups described below. (See 'Isoniazid and rifapentine (3HP)' below.)
For patients with contraindications to use of rifamycins (such as drug-drug interactions or hypersensitivity), isoniazid monotherapy (for six or nine months) is a reasonable alternative regimen.
A discussion of the available data on the efficacy for these regimens is presented below (see 'Regimen efficacy' below). Dosing is summarized in the table (table 4).
Important considerations with respect to regimen selection and administration include:
●RIF and RPT have significant interactions with many medications including the following: warfarin, oral and other hormonal contraceptives, some antihypertensives, some antiarrhythmics, some antidepressants, some anticonvulsants, methadone, buprenorphine, and the protease inhibitor class of antiretroviral drugs. Specific interactions can be determined by use of the drug interactions program included within UpToDate. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)
●Regimens for treatment of TBI are associated with hepatotoxicity; the risk of hepatotoxicity is greatest with INH and less so for the rifamycin-based regimens. Additional side effects associated with rifamycins include rash and thrombocytopenia. (See 'Assess comorbidities' above and 'Monitoring and adherence' below.)
●Peripheral neuropathy occurs in up to 2 percent of patients taking INH due to interference with metabolism of pyridoxine and can be prevented with pyridoxine supplementation [21]. For individuals on an TBI regimen containing INH with risk factors for INH neurotoxicity (diabetes, uremia, alcoholism, malnutrition, HIV infection, pregnancy, seizure disorder), we coadminister pyridoxine (25 to 50 mg daily). We also administer pyridoxine to infants of breastfeeding mothers receiving INH.
●Important side effects of 3HP include hypersensitivity or flu-like symptoms (eg, light headedness, dizziness, headache, nausea or vomiting, syncope, rash, or angioedema); these occurred in 3.8 percent of patients treated with 3HP in one trial [22]. For this reason, 3HP usually is administered via directly-observed therapy (DOT), to facilitate side effect review and treatment withholding if needed. Self-administration of 3HP may be acceptable for patients who can reliably take their medications on schedule and inform their providers promptly of side effects (while withholding the next dose pending provider review) [22-24]. (See 'Isoniazid and rifapentine (3HP)' below.)
●Self-administered INH is frequently associated with poor adherence; for patients with poor adherence and contraindications to rifamycins, administration of INH via DOT may be the optimal approach.
●The risk of INH toxicity rises substantially with age [25]. Therefore, in older patients, a regimen without INH may be preferable.
RIF with pyrazinamide (PZA) should NOT be used for treatment of TBI because of the possibility of severe hepatotoxicity [26-30]; it was previously included in the CDC 2000 Guidelines [31]
High-incidence settings — Individuals without HIV infection in high-incidence settings (TB incidence rate ≥100 per 100,000 population) who may warrant TBI treatment consist of close contacts of TB cases, particularly children <5 years of age (table 5). For these individuals, we favor a rifamycin-based regimen (4R, 3HR, or 3HP) (table 4) (see 'Low-incidence settings' above); our approach differs from that of the World Health Organization, which favors the regimen of INH daily for six months or 3HP weekly for 12 weeks [8].
Issues related to treatment of TBI for individuals with HIV infection are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)
Regimen efficacy — Regimens for treatment of TBI are summarized in the table (table 4); the approach to selecting a regimen is described above. (See 'Selecting a regimen' above.)
Rifamycin-based regimens — In general, we favor rifamycin-based regimens over INH monotherapy, given the efficacy, favorable treatment completion rates, and relatively low hepatotoxicity rates of rifamycin-based regimens [6]. This approach is supported by a meta-analysis of 63 studies evaluating TBI treatment in the 2020 guidelines for treatment of TBI issued by the United States CDC and NTCA; odds ratios for risk of TB for patients treated with 4R, 3HR, 3HP, and INH for 6 months were 0.25, 0.33, 0.36, and 0.40, respectively [6]. These findings serve an update to an earlier meta-analysis published in 2017 [32].
The FDA announced detection of nitrosamine impurities in samples of RIF and RPT in August 2020. This is discussed further above. (See 'Selecting a regimen' above.)
Rifamycin-based regimens include RIF daily for four months (4R), INH and RIF daily for three months (3HR), and INH and RPT weekly for three months (3HP).
Rifampin (4R) — The efficacy of 4R for reducing the incidence of TB disease is estimated to be similar to that of INH monotherapy; 4R regimen is well tolerated, with good completion rates and a low rate of hepatotoxicity [6,32-40]. This was illustrated in a randomized trial including more than 6800 adults with TBI treated with 4R or 9H; 4R was not inferior to 9H for prevention of TB disease (<0.01 cases per 100 person-years in both groups) and was associated with a higher rate of treatment completion (79 versus 63 percent) and lower rate of adverse events (rate difference -1.1 percentage points for all events; 95% CI -1.9 to -0.4) [33]. RIF was associated with "rash or other allergy" in 0.2 percent of patients treated with 4R.
In addition, the cost for administration of 4R is lower than that of 9H. In one study including more than 6000 adults and 800 children, the ratios of costs for 4R versus 9H were 0.76 (95% CI 0.70-0.82) in high-income countries, 0.90 (95% CI 0.85-0.96) in middle-income countries, and 0.80 (95% CI 0.78-0.81) in African countries [41].
Isoniazid and rifampin (3HR) — Data on use of 3HR in patients without HIV infection are limited [39,42]. In a prospective randomized trial among individuals with HIV infection, 3HR provided 60 percent protection [43]. Although this regimen has not been studied in a large trial among persons without HIV infection, a meta-analysis of small studies in this population suggests that it is equally efficacious and not more toxic than INH for nine months [42].
Isoniazid and rifapentine (3HP) — RPT is a rifamycin derivative with a long half-life and greater in vitro potency against M. tuberculosis than RIF. Hypersensitivity is an important side effect, as discussed above. (See 'Selecting a regimen' above.)
3HP (given via DOT) was noninferior to daily INH for nine months (self-administered) in a randomized trial including more than 7700 predominantly individuals without HIV infection at high risk for progression from TB infection to TB disease in four low-incidence countries (Brazil, Canada, Spain, and the United States) with up to 33 months of follow-up [22]. Patients were ≥12 years of age and belonged to one of the following four high-risk categories:
●Close contact of patient with culture-confirmed contagious TB and positive tuberculin skin test (TST)
●Recent (within 2 years) conversion from negative to positive TST result
●Patients with HIV infection not on antiretroviral medications with positive TST or who have had close contact with known TB case (regardless of TST status)
●Positive TST with fibrotic changes on chest radiograph consistent with previously untreated TB
Most participants in the trial were presumed to be recently infected; contacts of infectious cases and recent TST converters made up approximately 96 percent of patients. Progression to TB disease occurred in 0.19 percent of patients who received combination therapy and 0.43 percent of patients who received INH. Hepatotoxicity was observed more frequently in the INH group (2.7 versus 0.4 percent), while "hypersensitivity" was observed more frequently in the combination therapy group than the INH group (3.8 versus 0.5 percent). The completion rates for the combination group and INH group were 82 and 69 percent, respectively. At least some of the higher completion rate for combination therapy (and thus some of the efficacy) can be attributed to administration via DOT, while INH was self-administered.
An association between 3HP and flu-like symptoms or other systemic drug reaction was observed [44]. These reactions occurred in 3.5 percent of mostly patients without HIV infection; risk factors included White race, older age, and lower body mass index. The reactions were serious (hypotension or syncope) in 0.3 percent of cases; none was associated with serious sequelae or death. This phenomenon remains poorly understood and difficult to predict; therefore, careful monitoring of patients on this regimen is important. (See 'Selecting a regimen' above.)
Similar findings have been observed in other studies describing implementation of 3HP for treatment of TBI. In one study, administration of 3HP with DOT to more than 3200 patients in 16 health care settings throughout the United States was associated with a treatment completion rate of 87 percent [45]. In another study by the New York City Health Department clinics (more than 300 patients) was associated with a significant increase in treatment completion (65 versus 34 percent) [46].
Administration of 3HP via DOT facilitates review for side effects and withholding treatment if significant side effects are suspected. Self-administered therapy is acceptable for patients who can reliably take their medications on schedule and inform their providers promptly of hypersensitivity or other potential serious side effect (while withholding the next dose pending provider review) [24]. This approach is supported by a randomized trial that included a subgroup of 774 patients with TBI in the United States treated with 3HP via DOT, self-administration, or self-administration with reminders; completion rates were 85, 78, and 77 percent, respectively [23]. However, the study was not powered for safety analysis and patients on this regimen still require monthly provider visits to review for signs or symptoms of hepatic or hematologic toxicity. Among 15 patients treated with 3HP between 2012 and 2016 who were hospitalized for adverse effects, 9 had hypotension and 5 had elevated serum aminotransferases; none died [47].
3HP should not be used for children <2 years of age or individuals with presumed infection with INH- or RIF-resistant TB [22,48].
Isoniazid monotherapy — The effectiveness of INH for reducing the incidence of TB disease (compared with placebo) in clinical trials is 60 to 90 percent. However, the efficacy in practice is lower (25 to 92 percent) because of adherence issues; therefore, we use INH only when a rifamycin-based regimen cannot be given [49,50]. Moreover, INH has a less favorable adverse event profile [51].
In the only study comparing the efficacy of different durations of INH therapy, six months of treatment was 65 percent effective and 12 months of treatment was 75 percent effective (but not statistically different from six months) in preventing TB among patients with radiographic abnormalities suggestive of inactive infection [52]. By extrapolation of data from randomized trials, the optimal duration of INH treatment for TBI has been determined to be nine months [3,31,52].
INH can also be given twice weekly, which facilitates direct observation [6]. In a retrospective study including more than 1300 children with TBI treated with intermittent directly observed preventive therapy (DOPT; biweekly INH or RIF for 2 to 3 months or 9 months), the efficacy of intermittent DOPT was 98 percent (minimum duration of follow-up 1.5 years) [53].
The most important side effect of INH is hepatitis; the incidence is about 1 per 1000 persons, although asymptomatic mild liver enzyme abnormalities are relatively common [54-56]. INH toxicity also increases substantially with age; therefore, 4R may be preferred for patients >50 years of age [25,40]. The most important risk factor for the development of INH-induced hepatitis is alcohol consumption; patients should be advised to abstain from alcohol while taking INH. In addition, all individuals on INH should be educated about the symptoms of hepatitis and instructed to stop taking the drug immediately and seek prompt evaluation of symptoms to reduce risk for progression to severe disease. (See 'Monitoring and adherence' below.)
INH interference with metabolism of pyridoxine leads to peripheral neuropathy in up to 2 percent of patients [21]. In the setting of conditions that can predispose to neuropathy (including diabetes, uremia, alcoholism, malnutrition, and HIV infection) as well as in the setting of pregnancy and seizure disorders, patients on INH should receive pyridoxine supplementation (25 to 50 mg daily). Pyridoxine should also be administered to infants of breastfeeding mothers receiving INH.
Monitoring and adherence — Issues related to baseline liver enzyme testing are discussed above. (See 'Assess comorbidities' above.)
Patients receiving TBI treatment should be seen at least monthly and monitored for clinical symptoms of hepatitis and other side effects [7]. Patients receiving treatment by DOT should be questioned at each dose about possible side effects [22]. For patients at risk for hepatitis, liver function tests should be monitored monthly at the time of clinical examination, following baseline assessment.
Patients receiving TBI treatment should be educated about the symptoms of hepatitis and instructed to stop the medication should such symptoms occur and to seek prompt evaluation of symptoms to reduce risk for progression to severe disease [57]. Symptoms of hepatitis include anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness or fever lasting three or more days, abdominal pain (particularly right upper quadrant discomfort), easy bruising or bleeding, or arthralgias [57].
Individuals with signs or symptoms suggesting hepatotoxicity should be evaluated clinically and with liver function testing.
INH and rifamycins should be discontinued for symptomatic patients with serum transaminase levels greater than three times the upper limit of normal or for asymptomatic patients with serum transaminase levels greater than five times the upper limit of normal [49]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)
Patients who develop a rash or unexplained bruising while taking a rifamycin should stop the medication pending clinical evaluation; rifamycins may be associated with rash and/or thrombocytopenia.
Adherence to prolonged therapy is a major challenge for patients undergoing treatment of TBI [37,58,59]. This issue is discussed in detail separately. (See "Adherence to tuberculosis treatment".)
Subsequent management — There is no definitive way to determine whether TBI treatment has been effective in eliminating the infection. TBI treatment with INH prevents up to 90 percent of subsequent TB disease [60].
If symptoms develop that raise the possibility of TB disease, evaluation should be pursued with chest radiograph and other investigation as outlined in detail separately. (See "Diagnosis of pulmonary tuberculosis in adults".)
In general, patients with documented positive TST do not benefit from repeat TST; once the test is positive, it typically remains positive. Repeating the test has some risk of severe reaction and no clinical utility. There are no additional mechanisms to evaluate for subsequent TB exposure in these individuals. Similarly, serial use of interferon-gamma release assay is limited by difficulties with interpretation. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
SPECIAL CIRCUMSTANCES
Drug-resistant TBI — Treatment of contacts of patients with drug-resistant TB depends on the spectrum of resistance (rifampin [RIF] monoresistant, isoniazid [INH] monoresistant, and multidrug resistant [MDR]):
●For contacts of patients with INH-monoresistant TB, treatment consists of 4R; regimens containing INH cannot be presumed to be effective.
●For contacts of patients with RIF-monoresistant TB, treatment consists of INH daily for nine months.
●For contacts of patients with MDR-TB, treatment should be individualized based on the susceptibility profile of the index case, as discussed below.
There are limited data on the effectiveness of treatment of TBI in persons presumed or known to be infected with MDR-TB; the optimal approach is uncertain [61-63]. Suggested regimens include fluoroquinolone-based regimens or at least two drugs to which the suspected infected organism is susceptible [64-66]. Options are summarized in the table (table 6). Pyrazinamide (PZA) given with a second drug has been associated with individual cases of severe hepatotoxicity and should be avoided [8,27-29,67].
A fluoroquinolone-based regimen (levofloxacin 750 to 1000 mg orally once daily or moxifloxacin 400 mg orally once daily) may be effective in preventing TB in MDR-infected contacts if the source case isolate is known or suspected to be fluoroquinolone susceptible [65,68,69]. This was observed in an observational cohort study in which 119 infected contacts received a 12-month fluoroquinolone-based regimen (moxifloxacin or levofloxacin alone or with either ethambutol or ethionamide, based on source case isolate drug susceptibility testing); none developed disease [70].
The duration of treatment of TBI due to MDR strains has not been studied; 6 to 12 months is reasonable [31]. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)
Some data suggest INH may provide some protection against progression of TB disease among contacts of individuals with drug-resistant pulmonary TB; the mechanism for such protection is unclear [71].
Interrupted TBI therapy — In general, it is preferable that patients do not interrupt therapy. For circumstances in which the specified number of doses cannot be administered within the target period, a determination should be made regarding continuing the same regimen for the remaining duration of time or restarting treatment from the beginning. The earlier the interruption in the course of treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning.
In general, for treatment of TBI, treatment may be resumed where it was left off if less than two months were missed; treatment for TBI should be reinitiated from the beginning if more than two months were missed. There are no data regarding the impact of treatment interruptions on the effectiveness of any of the TBI treatment regimens.
TBI therapy after presumptive treatment for TB disease — TBI may be inferred for patients initiated on presumptive therapy for TB disease (based on positive Mantoux or tuberculin skin test, epidemiologic exposure, etc) but in whom subsequent cultures are negative and there is no clinical response to treatment. The time of initial phase combination therapy administered can be applied to the total duration of treatment for TBI. Options include stopping treatment if RIF and PZA have been included in the treatment regimen for at least two months or continuing treatment with RIF and/or INH until one of the recommended TBI treatment regimens has been completed [72].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Tuberculosis (The Basics)")
●Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Terminology – Tuberculosis (TB) terminology is inconsistent in the literature (table 1). The following terms are used in this discussion (see 'Terminology' above):
•Tuberculosis infection (newer term for latent tuberculosis; TBI)
•Tuberculosis disease (newer term for active tuberculosis)
●Whom to treat – The goal of testing for TBI is to identify individuals who are at increased risk for the development of TB and therefore would benefit from treatment of TBI (table 2). The decision to treat for TBI should be individualized, as risk may outweigh benefit in some cases. (See 'Whom to treat' above.)
●Prior to treatment – Prior to starting treatment for TB infection, we ensure that there are no signs or symptoms of TB disease based on history (eg, fever, cough, weight loss, night sweats), physical examination, and chest radiography (algorithm 1). This evaluation is important to avoid undertreatment of TB disease, which can lead to emergence of drug resistance. (See 'Prior to treatment' above.)
●Regimen selection – (see 'Selecting a regimen' above)
•Clinical approach
-For treatment of TBI in most nonpregnant adults without HIV infection, we suggest a rifamycin-based regimen over isoniazid (INH) monotherapy (table 4) (Grade 2B) given the efficacy, favorable treatment completion rates, and relatively low hepatotoxicity rates of rifamycin-based regimens. The choice of regimen is based on administration schedule and expected toxicity.
Rifamycins have drug interactions with many common medications; consult the drug interactions program to identify and manage potential interactions.
INH monotherapy is a reasonable alternative for patients with contraindications to rifamycins (such as drug-drug interactions or hypersensitivity) or concern for nitrosamine impurities in rifamycins (table 4). Directly observed therapy is preferable given the poor adherence with self-administered INH.
-We recommend against the use of rifampin with pyrazinamide for treatment of TBI because of the risk for severe hepatotoxicity (Grade 1B).
•Nitrosamine impurities − Given detection of nitrosamine impurities in samples of rifampin (RIF) and rifapentine announced by the US Food and Drug Administration in August 2020, INH monotherapy should be considered as an alternative regimen for patients with newly diagnosed TBI. However, for individuals at highest risk of new TB infection or risk of reactivation (such as close contacts, recent converters, immunocompromised individuals, and those who will be receiving tumor necrosis factor-alpha inhibitors), use of rifamycin-containing regimens may be considered after evaluating potential risks and benefits in discussion with individual patients.
•Pyridoxine supplementation for patients on INH − Pyridoxine supplementation (25 to 50 mg daily) prevents INH-induced peripheral neuropathy; it is especially important for patients with conditions that predispose to neuropathy (including diabetes, uremia, alcoholism, malnutrition, and HIV infection), pregnant patients, and those with a seizure disorder. Pyridoxine should also be administered to infants of breastfeeding mothers receiving INH.
●Monitoring − (see 'Monitoring and adherence' above):
•Adverse effects – Both INH and rifamycins are hepatotoxic, though the risk of hepatitis is greater with INH. Rifamycins are also associated with rash and thrombocytopenia.
•Clinical approach – During treatment, patients are seen at least monthly and monitored for hepatitis and other toxicities. All patients are informed of the signs and symptoms of hepatitis and advised to stop therapy and seek prompt evaluation should they occur. For patients at increased risk for hepatitis (table 3), we measure liver enzymes at baseline and monthly while on therapy.
We discontinue treatment in symptomatic patients with serum transaminase levels >3 times the upper limit of normal (ULN) and in asymptomatic patients with serum transaminase levels >5 times the ULN.
●Drug-resistant TBI − We suggest treating contacts of patients with INH-monoresistant TB with RIF daily for four months (4R) (Grade 2C). We suggest treating contacts of patients with RIF-monoresistant TB with INH daily for nine months (Grade 2C). Treatment of contacts of patients with multidrug-resistant TB depends on the individual pattern of resistance; suggested regimens are summarized in the table (table 6). (See 'Drug-resistant TBI' above.)
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