Q&A: CDC updates latent TB recommendations for first time in 20 years
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The CDC and National Tuberculosis Controllers Association, or NTCA, has published updated recommendations for latent tuberculosis, or LTBI, in the MMWR for the first time since 2000.
To develop the new recommendations, CDC and NTCA convened a committee that conducted a systematic review of the literature for clinical trials of LTBI treatment regimens. They evaluated evidence quality via Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. They also performed a network meta-analysis to evaluate regimens that had not been directly compared in clinical trials.
Treatment regimens in the guidelines include three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. The updated guidelines are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to rifampin or isoniazid.
We spoke with Infectious Disease News Editorial Board Member David L. Cohn, MD, attending physician at Denver Public Health and professor of medicine in the division of infectious diseases at the University of Colorado School of Medicine, about major changes to the guidelines and the process of updating the recommendations. – by Eamon Dreisbach
Q: How large is the burden of latent TB globally and in the United States?
A: It is estimated that one-fourth of the world’s population (about 2 billion persons) are infected with Mycobacterium tuberculosis, including 13 million persons in the U.S. Most of these persons are asymptomatic and are classified as having latent tuberculosis infection.
Q: Latent TB treatment guidelines were last published in 2000. What developments have occurred since then?
A: Since the last ATS/CDC guidelines were published in 2000, one preferred regimen, rifampin and pyrazinamide given for 2 months, was no longer recommended in 2003 owing to case reports of severe hepatotoxicity that occurred after widespread implementation of those guidelines.
Since then, several studies have evaluated rifamycin-containing regimens used for shorter courses (3-4 months) than the standard regimen of isoniazid for 9 months that was established in the 2000 guidelines. In particular, two large multinational randomized controlled trials (RCTs) conducted in the past 2 decades showed that the rifamycin regimens were noninferior in terms of efficacy and had less toxicity and higher completion rates than isoniazid. The CDC-sponsored PREVENT TB trial compared isoniazid plus rifapentine given once-weekly for 3 months (3HP) with isoniazid daily for 9 months (9H) and the Canadian Institutes of Health Research trial compared rifampin daily for 4 months (4R) with isoniazid for 9 months. In addition, several other RCTs were performed, including the evaluation of isoniazid and rifampin for 3 months (3HR).
A systemic literature search was carried out by the LTBI Treatment Guidelines Committee. Included in the analyses were 55 RCTs of effectiveness and 31 studies of hepatotoxicity (in both HIV-positive and HIV-negative persons) published from 1962 to 2018. A network meta-analysis evaluated 63 studies of 16 different treatment regimens.
Q: What are the major changes to the recommendations?
A: The major changes are that short-course rifamycin-based regimens (3HP, 4R and 3HR) are now preferred regimens over longer-course isoniazid regimens (9H and 6H), which are considered alternative regimens for treatment of LTBI. These preferences are based on the cumulative evidence showing similar efficacy, favorable tolerability and high completion rates with the rifamycin regimens, which should result in greater effectiveness in clinical settings. The GRADE Strength of Recommendations and Quality of Evidence for the respective regimens are shown in Table 3 of the guidelines.
The once-weekly 3HP regimen facilitates the use of directly observed therapy, but can also be self-administered. The daily regimens, 4R and 3HR, are intended for self-administered therapy. The guidelines also emphasize that rifampin and rifapentine are not interchangeable, with different pharmacokinetics and drug-drug interactions.
Q: What audience do you think should read these guidelines?
A: All clinicians who are involved in the care of TB patients, their contacts (ie, infectious diseases and pulmonary physicians, health department physicians and nurses) and most primary care providers should read these guidelines. In particular, any provider who cares for persons at risk for LTBI and TB should know about testing and treatment for LTBI. This includes populations with higher rates of infection than the general population (ie, persons who were born in or lived in countries where TB is common and persons experiencing homelessness or incarceration or using injection drugs) and persons with high rates of progression from LTBI to active TB (ie, HIV-positive patients, recent contacts of patients with TB, fibrotic lesions on chest x-rays, diabetes mellitus, low body mass, renal disease and other immunocompromising conditions or use of immunosuppressive drugs).
Elimination of TB in the U.S. will not occur unless there is more widespread treatment of LTBI by primary care clinicians. It is hoped that this treatment is facilitated by the use of shorter and safe regimens. Patient advocacy groups involved in TB care and treatment and other populations at risk should also become familiar with the guidelines. For persons who are being offered or are undergoing treatment for LTBI, user-friendly and culturally sensitive material should be available. It has always been challenging to explain to patients why they should take preventive medications for months when they feel well.
Guidelines on practical considerations for testing and treatment of LTBI, which will include information on populations at risk and implementation, will be forthcoming later this year from the NTCA.
Q: Is 20 years too long to update treatment guidelines? Was there a particular reason for the gap in updates?
A: Yes and Yes.
The initial meeting to plan revised LTBI guidelines occurred at the ATS meeting in 2011, which set out to draft a comprehensive document — “who” to test and treat for LTBI, ”what” to treat with and “how” to implement. The guidelines were co-sponsored by ATS, IDSA and CDC. Over the course of the next 4 years, evidence tables (as in the current supplement) were collated and several drafts of the document were written and revised, with several delays.
In late 2016, both ATS and IDSA withdrew support for the guidelines, contending that they were out of date. They were not, in the opinion of all members of the writing team. There were several reasons for the delays, reasons which are not unique to this project — inadequate sustained time and attention devoted to the project, largely because the work is unfunded and relies on busy clinicians and researchers who have competing priorities; insufficient or intermittent support for literature search, methodological assistance, face-to-face meetings and/or general organization to stay on-task; lack of training or sufficient education of chairs and members about the time commitment required to write and complete a practice guideline; the cumbersome, inefficient and unfamiliar requirements of the GRADE system, the current methodology used by many (but not all) organizations to fulfill Institute of Medicine standards for guideline development; and striving to create an overly ambitious document, parts of which were incompatible with GRADE.
I believe this project was discontinued more because of the bureaucratic process and poor communication than by the quality of the work. ATS has made improvements in providing more administrative support, training a cadre of methodologists to assist in guidelines and encouraging applicants to limit the number of questions in guideline proposals.
In 2017, several members of the original writing team, along with other experts from CDC, NTCA and methodologists, reconvened to create a streamlined document focused on “what” to treat with. Following the addition of data from two RCTs and the aforementioned updated meta-analyses, the revised guidelines were completed, resulting in their recent publication in MMWR.
Disclosure: Cohn reports no relevant financial disclosures.
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