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Treatment of Latent
Tuberculosis Infection—An
Update
Moises A. Huaman, MD, MSca,b,c,*, Timothy R. Sterling, MDc,d
INTRODUCTION
Latent tuberculosis infection (LTBI) is defined by the presence of detectable immune responses to Mycobacterium tuberculosis antigens with no clinical evidence of active TB disease. 1 It has been estimated that one-quarter of the world population has LTBI; however, there are wide variations in the rates of LTBI across regions. 2 In high-income countries, the incidence of active TB disease has continued to decline over the recent decades, 3,4^ but the prevalence of LTBI has remained stable. For example, in the United
States, 4% to 5% of the population was esti- mated to have LTBI in 2011 to 2012, 5 similar to prevalence rates reported in 1999 to 2000. 6 This indicates a persistent reservoir of M tuber- culosis infection even in countries where active disease is less frequent. Because a majority of new TB cases in these settings are a result of reactivation of remote LTBI rather than recent infection, 7–9^ intensification of LTBI screening and treatment strategies is recognized as a crucial component of TB elimination in low TB prevalence settings. 3,10,11^ Modeling studies also show the significant contribution of LTBI
Disclosure Statement: The authors have no potential conflicts to disclose. Financial Support: This work was supported in part by the National Center for Advancing Translational Sciences (KL2 TR001426 to M.A. Huaman). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or the institutions with which the authors are affiliated. a (^) Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medi- cine, University of Cincinnati, 200 Albert Sabin Way, Room 3112, Cincinnati, OH 45267, USA; b^ Hamilton County Public Health Tuberculosis Control Program, 184 McMillan Street, Cincinnati, OH 45219, USA; c (^) Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, A- Medical Center North, Nashville, TN 37232, USA; d^ Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Vanderbilt University, 1161 21st Avenue South, A-2209 MCN, Nash- ville, TN 37232, USA
- Corresponding author. Department of Internal Medicine, Division of Infectious Diseases, University of Cincin- nati, 200 Albert Sabin Way, Room 3112, Cincinnati, OH 45267. E-mail address: moises.huaman@uc.edu
KEYWORDS
(^) Latent tuberculosis infection (^) Treatment (^) Tuberculosis (^) Prevention and control (^) Isoniazid (^) Rifampin (^) Rifapentine (^) Review
KEY POINTS
Treatment of latent tuberculosis infection is an important component of tuberculosis control and elimination. Treatment regimens for latent tuberculosis infection include once-weekly isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily isoniazid plus rifampin for 3 months to 4 months, and daily isoniazid for 6 months to 9 months. Isoniazid monotherapy is efficacious in preventing tuberculosis, but the rifampin-containing and rifapentine-containing regimens are shorter and have similar efficacy, adequate safety, and higher treatment completion rates.
Clin Chest Med 40 (2019) 839– https://doi.org/10.1016/j.ccm.2019.07.
0272-5231/19/Ó 2019 Elsevier Inc. All rights reserved.^ chestmed.theclinics.com
treatment in controlling the TB epidemic in high burden settings. 4,12^ Ongoing efforts to target LTBI are challenged by limitations of current diagnostic tests to identify LTBI and persons at highest risk for progression to TB disease, po- tential toxicities of available LTBI therapies, sub- optimal treatment adherence rates, and limited resources of TB control programs. 13– This article reviews current LTBI treatment regi- mens. The primary focus is on LTBI treatment in low TB prevalence settings, such as the United States and Canada. Sections of LTBI management in special populations (ie, HIV-positive individuals, transplant patients, pregnant women, children, and contacts of multidrug-resistant TB) and con- siderations for LTBI treatment in high TB preva- lence settings are included.
INDICATIONS FOR LATENT TUBERCULOSIS
INFECTION SCREENING AND TREATMENT
LTBI screening is indicated in populations with a high risk of progression to TB disease and popula- tions with increased risk for LTBI (Box 1).1,16,17^ Per- sons at increased risk of progression to TB disease include household contacts of confirmed pulmo- nary TB cases (in particular, children <5 years of age), persons living with human immunodeficiency virus (HIV)/AIDS (PLWHA), patients initiating anti– tumor necrosis factor (TNF)-a therapy, candidates
for hematologic or solid organ transplant, patients receiving dialysis, and patients with silicosis.^1 In low TB prevalence settings, populations at increased risk for LTBI may include immigrants from countries with high TB prevalence, health care workers, persons who live in high-risk congre- gate settings such as homeless shelters or correc- tional facilities, and users of illicit drugs.1,16, Recently, diabetes mellitus has been identified as a risk factor for LTBI and progression to TB dis- ease18,19; however, routine LTBI screening in dia- betic patients is not recommended by current World Health Organization guidelines.^1 Screening tests for LTBI include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). 20 Readers can refer to Michelle K. Haas and Robert W. Belknap’s article, “Diagnostic Tests for Latent Tuberculosis Infection,” in this issue for a discussion on LTBI diagnosis and testing modalities.
LATENT TUBERCULOSIS INFECTION TREATMENT REGIMENS
Four main antimicrobial regimens are currently available for LTBI treatment: isoniazid monother- apy, rifampin monotherapy, isoniazid plus rifampin in combination, and isoniazid plus rifapentine in combination (Table 1). Isoniazid monotherapy for 6 months to 12 months has been used for de- cades, and its efficacy in preventing progression to TB disease is approximately 90%.^21 Its overall effectiveness, however, has been hindered by low adherence and completion rates due to its prolonged duration and hepatotoxicity risk. 22, Shorter rifamycin-based regimens have similar efficacy and are increasingly used. These regi- mens are associated with improved completion rates as well as reduced risk of hepatotoxicity compared with isoniazid monotherapy. 24 Impor- tantly, studies have not shown an increased risk of developing isoniazid-resistant or rifamycin- resistant TB disease after receiving LTBI treatment regimens that contain these drugs. 25,
Isoniazid Daily for 6 Months to 12 Months
Isoniazid inhibits the synthesis of mycolic acids, which are essential components of the mycobac- terial cell wall. 27 Isoniazid monotherapy has been considered standard of care for LTBI treatment for several decades. 28,29^ Multiple studies have demonstrated the TB preventive efficacy of this drug. Isoniazid is administered at a dose of 5 mg/kg/d (conventional adult dose, 300 mg daily). 30 A meta-analysis of randomized controlled trials showed that the odds ratios of TB disease in persons with LTBI treated with 6 months
Box 1 Populations at risk of latent tuberculosis infection and tuberculosis disease
Contact of pulmonary TB cases Immigrants from high-burden TB areas Persons with HIV infection Transplant candidates Patients receiving hemodialysis Patients starting TNF-a inhibitors Patients with silicosis Homeless individuals Correctional facilities Health care workers Injection drug users Other agencies include additional populations at risk, such as persons receiving immunosuppression other than anti-TNF treatment. 17,34^ Recent LTBI test conver- tors are at highest risk of TB progression within the first 2 years after infection. Data from World Health Organization. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva, Switzerland. 2018.
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were followed-up to 28 months for the develop- ment of active TB. The rates of confirmed and clin- ically diagnosed TB disease were similar between the study groups and thus rifampin was deter- mined to be noninferior to isoniazid for TB preven- tion. Rifampin was associated with higher treatment completion rates than isoniazid (78.8% vs 63.2%). As shown in a prior smaller trial, 40 rifampin had a more favorable safety profile, including lower frequency of grade 3 to grade 4 hepatotoxicity events that required permanent drug discontinuation compared with isoniazid (0.3% vs 1.8%).^38 Rifampin may cause gastrointestinal symptoms (ie, abdominal pain and nausea), dermatologic re- actions, hypersensitivity reactions, hematological side effects, and hepatotoxicity. Urine and other body fluids may develop an orange discoloration, which can lead to staining of soft contact lenses and dentures. 34 Rifampin is a potent CYP3A inducer and may affect the metabolism of several drugs, including antiretrovirals, anticonvulsants, warfarin, azole antifungals, methadone, cyclo- sporine, and other immunosuppressants. 21, Therefore, checking for potential drug-drug interactions is advised when considering rifampin for LTBI.
Isoniazid and Rifampin Daily for 3 Months to 4 Months
A meta-analysis showed that the odds ratio of TB disease in persons with LTBI treated with daily isoniazid plus rifampin for 3 months to 4 months was 0.53 (95% credible interval, 0.36–0.78) compared with placebo. 31 Randomized trials have compared 3 months to 4 months of daily isoniazid plus rifampin to 6 months to 12 months of daily isoniazid monotherapy in HIV-positive and HIV-negative persons. 41–45^ Overall, similar TB prevention efficacy rates and safety profiles have been reported for the isoniazid plus rifampin combination regimen compared with standard isoniazid monotherapy.^46
Isoniazid and Rifapentine Once Weekly for 3 Months
Rifapentine is a rifamycin derivative with a longer half-life and increased potency compared with rifampin. 47,48^ In the Tuberculosis Trials Con- sortium Study 26/AIDS Clinical Trials Group 5259 (PREVENT TB), 7731 high-risk individuals with positive TST (contacts of pulmonary TB cases, recent TST convertors, PLWHA, and presence of fibrosis on chest radiograph) were randomized to receive 3 months of directly observed isoniazid, 900 mg, and rifapentine, 900 mg, once weekly,
or 9 months of isoniazid, 300 mg, daily monother- apy. 49 Participants were followed for 33 months. The isoniazid-rifapentine combination regimen was noninferior to isoniazid in preventing TB disease. The risk of hepatotoxicity was lower in the isoniazid-rifapentine combination group compared with isoniazid (0.4% vs 2.7%). Treat- ment completion rates were higher with the isoniazid-rifapentine combination than with isoni- azid (82.1% vs 69%). Similar completion rates have been reported among patients receiving the 3-month isoniazid-rifapentine regimen for LTBI in US TB control programs after its implementation in routine practice. 50 Based on the PREVENT TB trial design, the isoniazid-rifapentine regimen initially was administered only by directly observed therapy (DOT). A recent study, however, compared the isoniazid-rifapentine regimen given by DOT versus self-administered therapy (SAT).^51 Among US sites, once-weekly isoniazid-rifapen- tine given as SAT achieved similar treatment completion rates and safety outcomes as DOT; therefore, this regimen is now recommended as SAT by Centers for Disease Control and Preven- tion (CDC) guidelines. 52 Rifapentine is a potent CYP3A inducer (approximately 85% as potent as rifampin). Rifapentine and rifampin share similar drug-drug interaction and toxicity profiles. 53
INITIAL ASSESSMENT
Patients found to have LTBI should be evaluated by health care provider teams with experience in managing LTBI to rule out active TB and discuss implications of the diagnosis, risk of TB reactiva- tion, and available treatment options. A detailed history of TB risk factors, presence of comorbid- ities, and current medications should be obtained. Electronic decision support tools that provide personalized estimates of annual and cumulative risks of progression to TB disease, such as the Online TST/IGRA Interpreter (www.tstin3d.com), are available to assist patients and providers. 54, HIV testing is advised in all patients with LTBI. Baseline liver function tests should be considered in patients with baseline liver disease and/or risk factors for hepatotoxicity. Women of childbearing potential should be screened for pregnancy. Pa- tients in whom rifamycin-containing regimens are considered should have their current list of medi- cations analyzed for potential drug-drug interac- tions. Providers should discuss potential side effects of LTBI therapy and inform patients of signs and symptoms that require medical attention. Re- sources for educating patients on LTBI and avail- able therapies can be found at the CDC Web site (www.cdc.gov/tb/topic/treatment/ltbi.htm).
842 Huaman & Sterling
For the 3-month isoniazid plus rifapentine regimen, the decision on SAT versus DOT should be based on patient age, medical history, social circum- stances, risk factors for TB disease progression, and program resources. 52
LATENT TUBERCULOSIS INFECTION
TREATMENT MONITORING
Patients who initiate LTBI treatment should be routinely monitored for medication adherence and tolerability. The CDC recommends monthly visits to assess medication adherence and signs or symptoms of drug toxicity. 34 No laboratory tests are routinely ordered at follow-up visits, unless there is a clinical indication and/or concern for drug toxicity. In patients with abnormal baseline liver enzymes and/or at risk for hepatotoxicity, pe- riodic laboratory monitoring is recommended. 34 LTBI drugs should be held if a patient is symptom- atic and transaminase levels exceed 3 times the upper limit of normal or if asymptomatic and trans- aminase levels are greater than or equal to 5 times the upper limit of normal. Patients who develop signs or symptoms of active TB disease should be screened with a chest radiograph even if they are receiving LTBI treatment.
SPECIAL POPULATIONS
Persons Living with Human Immunodeficiency Virus/AIDS
HIV/AIDS carries a significant risk of progression to TB disease. It is estimated that in the absence of antiretroviral therapy (ART) as many as 10% of PLWHA with LTBI coinfection may develop TB dis- ease each year. 56,57^ The risk of progression to active TB among PLWHA on ART and optimal viro- logic response remains higher than the general population. 58 ART and treatment of LTBI both decrease the risk of TB among PLWHA 59–62^ ; thus, both are indicated. 63 Isoniazid monotherapy has been the preferred LTBI treatment regimen for PLWHA given its proved efficacy. 34,63^ A meta- analysis showed that isoniazid decreased the inci- dence of TB disease in 64% among PLWHA with a positive TST. 64 The 3-month once-weekly isoni- azid plus rifapentine regimen is noninferior to isoni- azid monotherapy in PLWHA who have not yet started ART 65 and can be used in PLWHA taking compatible ART, such as efavirenz-containing or raltegravir-containing regimens. 66,67^ Additional investigation is needed to determine the safety of once-weekly isoniazid plus rifapentine in PLWHA receiving dolutegravir-containing ART, because a severe flulike syndrome occurred in 2 of 4 healthy volunteers. 68 A recent trial (AIDS Clinical Trials
Group 5279) showed that an ultrashort course of 1 month of daily isoniazid, 300 mg, and rifapentine, 300 mg to 600 mg, was noninferior to 9 months of isoniazid for TB prevention in PLWHA (most of the study participants were living in high TB burden settings and were TST-negative). 69 The 1-month daily isoniazid-rifapentine regimen had fewer adverse events and higher treatment completion rates than 9 months of isoniazid. In PLWHA in settings with high TB prevalence, 36 months of isoniazid has been associated with a greater reduction in the risk of incident TB dis- ease than 6 months of isoniazid 70 ; however, the potential toxicities and adherence difficulties of such prolonged TB preventive therapy have made its implementation challenging.
Transplant Candidates and Persons Receiving Tumor Necrosis Factor–a Inhibitors
Transplant candidates found to have LTBI should receive one of the recommended LTBI treatment regimens, ideally prior to transplantation. 71 If transplantation occurs prior to LTBI treatment completion, treatment should be resumed after transplant as soon as medically feasible to com- plete the originally planned duration. Most of the clinical experience in transplant candidates with LTBI has been with isoniazid monotherapy. Case series of kidney, liver, and heart transplant candi- dates receiving the 3-month isoniazid-rifapentine regimen suggest adequate completion rates and tolerability in selected patients. 72–74^ Close follow- up is required in transplant candidates who initiate LTBI treatment to monitor for side effects and treatment adherence. Persons initiating TNF-a inhibitors should be systematically tested and treated for LTBI. 1 The American College of Rheumatology recommends completing at least 1 month of LTBI treatment prior to starting or resuming TNF-a inhibitors and other biologic agents in patients with rheumatoid arthritis. 75
Pregnant Women
Current CDC guidelines recommend considering LTBI treatment in pregnant women who are HIV positive or recent TB contacts. 34 In pregnant women not at high risk of progression to TB, LTBI treatment may be delayed until 2 months to 3 months postpartum. Isoniazid has been the preferred regimen for LTBI treatment during preg- nancy. 1,34^ Rifampin is an alternative option. Both isoniazid and rifampin are considered category C drugs during pregnancy. Whether to initiate or delay LTBI treatment during pregnancy should be a joint decision with each individual patient,
Treatment of Latent Tuberculosis Infection 843
(NCT02980016), which is comparing the 3-month isoniazid-rifapentine regimen given in annual cycles for 2 consecutive years with standard 3-month isoniazid-rifapentine or 6 months of isoni- azid given as single cycles. Novel vaccination strategies are under development, because the only licensed TB vaccine available (bacillus Calm- ette-Gue´ rin) does not provide substantial protec- tion against pulmonary TB disease. 90 A phase 2b trial of an adjuvant subunit vaccine containing 2 M tuberculosis antigens showed 54% efficacy in preventing TB disease development among HIV-negative adults with LTBI from endemic areas. 91 Readers can refer to Lisa Stockdale and Helen Fletcher’s article, “The Future of Vaccines for Tuberculosis,” in this issue for further discus- sion on the future of vaccines in TB prevention. Targeted host–directed therapies that enhance immune responses to M tuberculosis may offer opportunities as future adjuvant and/or primary TB preventive strategies. 92,
SUMMARY
Regimens of isoniazid, rifampin, or combinations of isoniazid plus rifampin or rifapentine are available for treating LTBI. Rifamycin-based therapies are shorter and better tolerated than isoniazid mono- therapy and thus are important tools to prevent TB disease and contribute to ending the TB epidemic. Novel vaccine strategies, host immunity–directed therapies, and ultrashort antimicrobial regimens for TB prevention are under evaluation.
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