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1 month of TB prophylaxis as effective as 9 months
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BOSTON — A 1-month antibiotic regimen to prevent active tuberculosis in patients living with HIV was just as effective and caused fewer adverse events than a standard 9-month regimen, according to results of a phase 3 clinical trial presented at CROI.
Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in a press release that the findings “have the potential to change clinical practice by offering people living with HIV who are at risk of developing active tuberculosis an additional, shorter-duration prevention option that is safe, works well and may be more convenient.”
TB, which is the leading cause of mortality from an infectious disease worldwide, accounts for 40% of deaths among people living with HIV (PLWH), according to WHO. HIV has been identified as a significant risk factor for the progression from latent to active TB. Prophylactic TB therapy is effective at preventing the development of active TB disease, according to researchers, but 6- to 9-month courses of daily isoniazid, which are standard in most countries, carry the risk of adverse events, such as liver damage. Patients also have difficulty adhering to these long treatment courses.
Researchers from the NIAID-funded AIDS Clinical Trials Group (ACTG) conducted a multicenter, randomized study called BRIEF TB/ACTG 5279 to compare a 1-month course of 450 mg to 600 mg of Priftin (rifapentine, Sanofi-Aventis) plus 300 mg of isoniazid with a 9-month course of 300 mg of isoniazid alone. They enrolled 3,000 PLWH aged 13 years and older in numerous countries, including Botswana, Brazil, Haiti, Kenya, Malawi, Peru, South Africa, Thailand, the United States and Zimbabwe. The participants either lived in an area with a high TB burden or tested positive for latent TB infection. Approximately half were taking ART at the beginning of the study in 2012. Patients were followed for approximately 3 years.
TB incidence was lower than expected in both groups, which was likely “a reflection of greater use of ART in the HIV study population” than the researchers had anticipated when planning the trial, according to ACTG Network Investigator Richard E. Chaisson, MD, a professor of medicine, epidemiology and international health at Johns Hopkins University School of Medicine. Active TB disease or death was reported in 32 participants in the 1-month arm and 33 in the 9-month arm, translating to an incidence rate of 0.65 per 100 person-years vs. 0.67 per 100 person-years (incidence rate difference = –0.023; 95% CI, –0.3 to 0.35). Regardless of the length of preventive TB treatment, active TB rates were higher among those who were not on ART at the start of the study and among those with a positive TB skin or blood test.
Among participants with a low CD4 cell count at the start of the study, latent TB progressed to active disease more often in those who received the 1-month course, although this finding was not statistically significant, the researchers said.
Both TB regimens were safe, and fewer adverse events were reported in the 1-month arm. According to the findings, adverse events associated with both rifapentine and isoniazid included nausea, vomiting, liver problems and skin rashes. The researchers noted that PLWH may be more prone to these events.
Results from the ACTG 5279 trial also showed that treatment adherence was significantly better among patients in the 1-month arm (97%) vs. the 9-month arm (90%).
“A major problem with current latent TB treatment is the long duration and high rates of early discontinuation in clinical practice,” Chaisson told Infectious Disease News. “If treatment can be cut down to 1 month, then patients have a greater chance for completion success and are less likely to develop side effects.”
ACTG researchers are finalizing their data collection and analysis and looking to publish their results in a high-impact journal, according to Chaisson.
“The BRIEF TB study evidence will need to be weighed with other research on treatment to prevent TB and should be implemented into international guidelines on TB disease prevention,” he said. “I believe we will see shorter courses of preventive TB therapy being widely used in people with HIV, and potentially those without HIV, within the next 1 to 2 years. – by John Schoen
References:
Chaisson RE, et al. Abstract 37LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston.
WHO. Tuberculosis. http://www.who.int/mediacentre/factsheets/fs104/en/. Accessed March 2, 2018.
Disclosures: Fauci reports no relevant financial disclosures. Chaisson reports being a consultant for Otsuka.
Perspective
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David L. Cohn, MD
The BRIEF TB study (A5279) is an important, well-conducted, multinational study with a heterogeneous population. It is the latest in a series of clinical trials to use shorter rifamycin-based regimens compared with longer courses of isoniazid for the treatment of latent TB infection (LTBI). This is one more study that shows we can shorten the length of treatment, resulting in higher completion rates, less toxicity and similar efficacy than with isoniazid.
Previous studies from the Tuberculosis Trials Consortium (TBTC) demonstrated that isoniazid and rifapentine given once-weekly for 12 weeks was safe and effective compared with isoniazid for 9 months in both HIV-negative and HIV-infected patients. That regimen has since been approved and recommended for the treatment of LTBI. Rifampin given daily for 4 months has higher completion rates and less toxicity than isoniazid for 9 months, and is widely used in several health departments in the U.S. and Canada. We await the results of a recently completed, large efficacy trial comparing these two regimens, conducted by the Canadian Institutes of Health Research. The major breakthrough in the BRIEF TB study is that it evaluated an “ultra short-course” regimen (ie, isoniazid and rifapentine for only 1 month), and it appears to be safe and noninferior compared with isoniazid for 9 months. That is great news, adding the shortest regimen of preventive therapy shown to be effective to our therapeutic armamentarium.
The incidence rate of TB in the trial was relatively low compared with recent prior studies of LTBI, attributed in part to the fact that 50% of participants were on ART. In addition, only 21% of the study population had positive tuberculin skin tests or interferon-gamma release assays; therefore, a significant number of study participants were not infected with Mycobacterium tuberculosis at the outset of the study. Nonetheless, the conclusions of the study are still valid, with the randomization and stratifications in the trial and similar event rates in the two arms.
This study was conducted in HIV-infected individuals, and we will want to know more about the safety and efficacy of this regimen in HIV-negative patients with LTBI. The TBTC is currently planning a trial to evaluate a 6-week regimen of rifapentine alone compared with standard-of-care control arms, and that study will largely include HIV-negative persons. This trial will provide additional safety data about the use of daily rifapentine for preventive therapy.
Following publication of the results of BRIEF TB, it is likely that isoniazid and rifapentine used for 1 month will eventually be incorporated into new guidelines on the treatment of LTBI. WHO recently released its updated guidance for program implementation, and the National Tuberculosis Controllers Association and CDC are also currently working on a new set of guidelines for the U.S. In the near future, based on high-quality evidence, providers will have several options of approved and recommended short-course, rifamycin-containing regimens for the treatment of LTBI.
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