Latent Tuberculosis

Joey Sweeney, PharmD, BCPS

Mycobacterium tuberculosis infects approximately 2 billion people throughout the world, while in the United States, 13 million people have the infection. Most of these people do not actively show symptoms and have what is referred to as latent tuberculosis infection (LTBI).  However, up to 10% of people with this latent disease progress to active tuberculosis (TB), representing 80% of TB cases in the country. If LTBI is treated appropriately, up to 80% of TB cases could be prevented.

Recently, the National Tuberculosis Controllers Association and CDC created a committee to update guidelines for treatment of LTBI in the United States.¹ The most recent guidelines were last updated in 2000, although there was also a 2003 recommendation against the 2-month rifampin plus pyrazinamide regimen because of hepatotoxicity risk. Several new treatment regimens have been created in these past 20 years.

In December 2017, the committee began a systematic literature review to determine the most effective and least toxic regimen. Only randomized controlled trials (RCTs) that included both prevention of TB disease progression and drug-related hepatotoxicity as data points were considered in the review. 

The Grading of Recommendations Assessment, Development, and Evaluation criteria were used to evaluate quality of evidence supplied by included RCTs. A robust statistical analysis allowed for indirect comparisons of treatment regimens and hepatotoxicity profiles across the 20,000-sample data set.

The analysis yielded three preferred treatment regimens with two alternative regimens. All five regimens assume that the patient’s M. tuberculosis strain is susceptible to isoniazid and rifampin (recommendations for treatment of resistant TB are specifically addressed elsewhere).²

Preferred regimens

The preferred three regimens are

• Three months of weekly isoniazid plus rifapentine given under direct observation (for all patients age >2 years, including HIV-positive patients),
• Four months of daily rifampin (for all patients if they are HIV negative), or
• Three months of daily isoniazid plus rifampin (for patients of all ages who are HIV positive if interactions with their HIV regimens allow).

There are disadvantages to the weekly isoniazid plus rifapentine regimen. One is increased cost of administration; external costs associated with transport to the clinic or office each week for 3 months may be prohibitive to patients. Another is pill burden; about 10 tablets/capsules would be administered at the weekly visit, compared with about 3 per day in other regimens. Drug interactions are also a concern.

Disadvantages to the daily rifampin regimen include drug interactions (which typically preclude use by patients on antiretroviral therapy for HIV infection) and increased potential for development of rifampin resistance in HIV-positive patients with low CD4+ lymphocyte counts.

Disadvantages to the daily isoniazid plus rifampin regimen include drug interactions and corresponding resistance in the presence of active TB.

These three primary regimens share the advantage of lower risk of hepatotoxicity because of the shortened course of treatment.

Alternative regimens

The two alternative regimens, 6 or 9 months of daily isoniazid, are longer in duration, which results in a greater risk of hepatotoxicity. The 6-month regimen is recommended for HIV-negative patients, while the 9-month regimen is recommended for both HIV-positive and -negative patients. Completion rates for these two regimens are low because of long duration (making compliance challenging) and hepatotoxicity.

These guidelines are a welcome update to the 2000 document because they contain data supporting shortened duration treatments that result in better efficacy and lowered toxicity. Pharmacists need to be vigilant when dispensing regimens that include a rifamycin, as they are not interchangeable across regimens.

It is important to understand that these guidelines are for patients with LTBI living in the United States. They do not apply to patients who live in environments with greater incidence of active TB.

References
1. Sterling TR. MMWR Recomm Rep. 2020;69(1):1–11
2. Nahid P, et al. Am J Respir Crit Care Med. 2019;200(10):e93–e142