By Carol A. Kemper, MD, FACP

Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center

Dr. Kemper reports no financial relationships relevant to this field of study.

SOURCE: Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69:1-11.

I explain to patients the risk of progression of their latent tuberculosis infection (LTBI) to active tuberculosis (TB) is about one in 13 people. As one ages, develops diabetes or kidney disease, or needs chemotherapy for any reason, that risk goes up to one in five. This usually grabs the patient’s attention. It is especially effective if a clinician tells a patient he or she may be contagious and infect their kids or coworkers. Somehow, if a clinician says the risk is 5% to 10%, it does not sound as bad. Maybe patients do not understand percentages. What they really may not understand is that despite all the modern care, the risk of mortality from active TB in the United States is a surprising 4%, worse than that of COVID-19.

In the United States, 80% of active TB cases are because of progression of untreated LTBI. At least 70% of active TB cases occur in foreign-born persons, many of whom do not want to believe they have been exposed to TB or understand the concept of latent TB. Capturing those individuals and treating them is important for controlling this infection. The last official LTBI treatment guidelines were written in 2000. Since then, a nine-month course of isoniazid (INH) has been considered the standard of care for the treatment of LTBI, and was the comparator regimen for all others. New guidelines, published in February 2020, escaped most physicians’ notice, arriving just as COVID-19 cases exploded. A committee formed by the Centers for Disease Control and Prevention (CDC) and the National Tuberculosis Controllers Association reviewed all available publications and treatment data, focusing on 63 publications with meaningful data on LTBI treatment. They systematically graded the outcomes, including the benefits, hepatotoxicity, adverse effects, patient preference, regimen complexity, and cost, as well as the quality of the published data.

The committee recommended three rifamycin-based regimens and two alternate six- or nine-month INH monotherapy regimens for LTBI treatment. They gave priority to shorter-course regimens with similar efficacy, higher rates of completion, and favorable tolerability compared with the former standard nine-month regimen of INH. Benefits and disadvantages presented are relative to this previous standard:

  • Three months of INH and rifapentine. Strongly recommended for adults and children > 2 years of age, including HIV-positive persons. Benefits: Equivalent effectiveness, less hepatotoxicity, shorter course, higher rates of completion when administered through directly observed therapy (DOT). Disadvantages: More adverse effects, higher cost, greater regimen complexity and higher pill burden, and lower rates of completion when not conducted through DOT.
  • Four months of rifampin. Strongly recommended for HIV-negative adults and children of all ages. Benefits: Similar effectiveness, less hepatotoxicity, fewer adverse effects, shorter course. Disadvantages: Numerous drug interactions, difficult to give in HIV infection, medication costs are higher (although offset by shorter course/fewer visits, may be more cost-effective on the whole).1
  • Three months of daily INH and rifampin. Conditionally recommended for adults and children of all ages, including HIV-positive persons when their regimen allows. Benefits: Similar effectiveness, lower risk of hepatotoxicity, and shorter course. Disadvantages: Higher rate of discontinuation for other adverse effects, risk for hepatotoxicity may be greater when both drugs given together, and numerous drug-drug interactions.
  • Six months of INH. Strongly recommended for HIV-negative adults and children of all ages. Conditionally recommended for HIV-positive adults and children. Benefits: Highly effective, but perhaps not quite as effective as nine or 12 months of INH (controlled data are lacking), inexpensive, shorter than nine months of INH. Disadvantages: Hepatotoxicity, longer treatment duration than the other proposed regimens, lower completion rates.
  • Nine months of INH. Conditionally recommended for adults and children of all ages, regardless of HIV status. Benefits: Highly effective, inexpensive. Disadvantages: Hepatotoxicity, longer treatment duration, lower completion rates.

These guidelines are for patients with LTBI presumed sensitive to therapy. Recommendations for treatment of exposure to drug-resistant strains of TB were published separately in 2019. However, the risk of INH resistance among those with culture-positive TB with no history of TB who were born in the United States is 5%. Among those who are foreign-born, it is 13%. INH resistance is highest in those born in Vietnam (18%), the Philippines (17%), and India (11%). Approximately 3% of all culture-positive TB cases in Santa Clara County were resistant to rifampin. Perhaps this is another reason to consider a rifamycin-based regimen.


  1. Bastos ML, Campbell JR, Oxlade O, et al. Health system costs of treating latent tuberculosis infection with four months of rifampin versus nine months of isoniazid in different settings. Ann Intern Med 2020; June 16. doi: 10.7326/M19-3741. [Online ahead of print].