Safer, shorter regimens needed for latent TB infection
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It is estimated that approximately one-quarter of the world’s population has latent tuberculosis infection (LTBI). Although effective therapies are available, these agents can have significant adverse effects that can complicate treatment.
Patients with LTBI are infected with Mycobacterium tuberculosis bacteria but do not have active TB disease. Those who have LTBI have an estimated lifetime risk for TB reactivation of 5% to 10% and therefore should be treated to prevent the development of active TB disease. In the United States, untreated LTBI accounts for 80% of TB disease cases.
Fortunately, antibiotic treatment of LTBI is approximately 90% effective when patients are compliant with the regimen and can complete the duration of therapy.
Current treatment recommendations from the CDC and WHO are provided in Table 1. Initially, LTBI treatment consisted of 6 to 12 months of daily isoniazid (INH). Although monotherapy with daily INH is still a treatment option in both the CDC and WHO guidelines, reduced patient adherence and development of medication side effects often reduce successful treatment. The advantage of newer regimens is shorter treatment durations, which result in higher completion rates. Studies have shown that the completion rate for 9 months of INH treatment ranges between 40% and 50%, whereas short-course LTBI regimens have been shown to have a completion rate up to 90%.
Evidence
A recent study by researchers for the CDC’s Tuberculosis Epidemiologic Studies Consortium reported the results of an observational cohort study describing the frequencies of LTBI regimens prescribed in the U.S. from July 2012 through May 2017. They also analyzed changes in prescribing over time to evaluate the adoption of CDC-recommended short-course LTBI regimens because they have similar efficacy, better tolerability and higher treatment completion compared with 6 or 9 months of INH treatment. They found that the three most used LTBI regimens were 4 months of daily rifampin (49%), 6 to 9 months of INH (32%) and 3 months of rifapentine and INH (13%). The remaining participants were prescribed nonstandard regimens. The selection of short-course regimens increased over the study period from 55% in 2013 to 81% in late 2016.
Treatment-associated adverse events have always been a concern during LTBI therapy. Most adverse events are mild, but life-threatening side effects can also occur. Adverse side effects can lead to poor adherence, as well as treatment interruptions that might impact successful completion of therapy. Hepatotoxicity has been the main concern, with the risk increasing with longer durations of therapy when using INH monotherapy. Rifamycin-based therapies have been associated with lower risks for hepatotoxicity but also may cause significant gastrointestinal symptoms, allergic reactions and bone marrow suppression, leading to leukopenia, thrombocytopenia and anemia.
A recent meta-analysis of LTBI treatment from Melnychuk and colleagues evaluated adverse effects associated with various LTBI regimens. It was designed to assist with clinical decision-making in starting patients on TB preventative treatment. They included 175 published studies in the analysis from many different countries, as well as different patient populations. Among adults, the incidence of any reported adverse event was 3.7%, with treatment discontinuation from hepatotoxicity occurring in 1.1%. The rates among children were much lower, with 0.4% reporting any adverse event, and treatment discontinuation in 0.02% of patients. Surprisingly, 3 months of rifapentine plus INH had the highest incidence of drug discontinuation due to adverse effects. The lowest incidence of all adverse events and drug discontinuation due to adverse effects was with 4 months of rifampin alone. Those treated with rifampin alone also had the lowest incidence of hepatotoxicity and the lowest incidence of drug discontinuation due to hepatic adverse effects.
Another recently reported study by Asare-Baah and colleagues evaluated factors associated with the discontinuation of short-course LTBI treatment. This study included 993 patients who were treated with either 3 months of weekly INH plus rifapentine administered by directly observed therapy (DOT) or 4 months of self-administered rifampin. Overall, the risk for treatment discontinuation reported in this study was 27%. Those treated with 4 months of rifampin had a significantly higher risk compared with those treated with 3 months of INH and rifapentine (31% vs 14%). The average time to discontinuation was 4 weeks after treatment initiation. Patients with a history of alcohol and recreational drug use were more likely to stop treatment with 4 months of rifampin but not with weekly INH and rifapentine, likely because this regimen was administered exclusively by DOT. Treatment discontinuation of INH and rifapentine was mainly due to adverse events, However, Latino ethnicity also was associated with a higher risk for discontinuation.
Although the results of these two studies are conflicting as to which short-course regimen has more toxicity, it is important to consider several other factors when starting a patient on LTBI therapy.
Advantages and barriers
Short-course LTBI treatment has definite advantages, but barriers to implementation do exist. Issues to consider are drug-drug interactions, costs and the high pill burden for rifapentine regimens. Disruptions in TB drug supply also have been problematic because of loss of manufacturers, lack of raw materials to manufacture the products and inefficient supply chains. These shortages may result in using treatment regimens that lead to lower patient compliance and worse outcomes. Providers must also decide between DOT vs. self-administered LTBI treatment regimens. Although weekly regimens are most often given by DOT, studies have shown self-administration has similar outcomes. Although DOT has advantages, it requires a lot of resources for TB programs, is often not accepted by patients and may not be available in all locations.
Despite significant advancement in LTBI treatments, continued research to develop safer and shorter regimens is necessary to help achieve TB control.
Reference:
- Asare-Baah M, et al. Open Forum Infect Dis. 2024;doi:10.1093/ofid/ofae313.
- Belknap R, et al. Ann Intern Med. 2017;doi:10.7326/M17-1150.
- Feng PI, et al. J Clin Tuberc and Other Mycobact Dis. 2023;doi:10.1016/j.jetube.2023.100382.
- Macaraig MM, et al. Int J Tuberc Lung Dis. 2018;doi:10.5588/ijtld.18.0035.
- Melnychuk L, et al. Clin Infect Dis. 2023;doi:10.1093/cid/ciad246.
- Sterling TR, et al. MMWR Recomm Rep. 2020;doi:10.15585/mmwr.rr6901a1.
- Wheeler C, Mohle-Boetani JM. Public Health Rep. 2019;doi:10.1177/0033354919826557.
- WHO. Latent tuberculosis infection: Updated and consolidated guidelines for programmatic management. https://www.who.int/publications/i/item/9789241550239. Published Feb. 15, 2018. Accessed Oct. 28, 2024.
For more information:
Jeff Brock, PharmD, MBA, BCIDP, is a Healio | Infectious Disease News Editorial Board Member and infectious disease pharmacy specialist at MercyOne Medical Center in Des Moines, Iowa. He can be reached at jeff.brock@mercyoneiowa.org.
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