Rifampicin Safer than Isoniazid for Latent Tuberculosis, Study Suggests

Rifampicin appears to be safer than isoniazid for treatment of latent tuberculosis for many patients, according to a new study by investigators at the McGill International TB Centre.

The study, published in The Lancet Infectious Diseases, examined 2 randomized controlled trials conducted in 9 countries from 2004 through 2014, including 3205 people who received 5 mg isoniazid daily for 9 months and 3280 who received 10 mg rifampicin daily for 4 months.

“I think the biggest takeaway from this research is that rifampicin appears to be very safe,” lead author Jonathon Campbell, PhD, of the Montreal Chest Institute and the McGill International TB Centre at the Research Institute of the McGill University Health Centre, told Contagion^®.

“It has significantly fewer adverse events than isoniazid, which are not associated with age. We've seen several rifamycin-based therapies—such as 3 months of once-weekly rifapentine and isoniazid or three months of daily rifampicin and isoniazid—compared to isoniazid, however none of them have been shown to be safer. Rifampicin given daily for 4 months is the first rifamycin-based therapy to have this characteristic. I think it's an important step forward to have safe, short, and effective latent tuberculosis regimens available to patients. Rifampicin is also available in all countries making this a truly universal therapy.”

The study, funded by the Canadian Institutes of Health Research, found that 86 (2.7%) of the patients who received isoniazid experienced adverse events compared with 50 (1.5%) of those who received rifampicin. Adverse events were associated with age in the isoniazid group but not the rifampicin group, for which adverse events were associated with inconsistent medication adherence and concomitant medication use.

“I think we were a bit surprised when we took a look at the age relationship with adverse events,” Campbell told Contagion^®. “You generally need a lot of patients to be able to tell if the trends you are seeing are 'real,' so with rifampicin we hadn't had this opportunity previously. With isoniazid we saw a significant increase in adverse event risk after the age of 35, but with rifampicin we did not see any increase in adverse events with older age.”

Adverse events included in the study were grade 1-2 rash or any grade 3-5 adverse event. Being age 35 and older was the only predictor of adverse events among the isoniazid group. Three-quarters of all hepatoxicity, which was associated with older age and elevated alanine aminotransferase levels before treatment, occurred within the first 4 months, the study noted. For patients receiving rifampicin, the odds of adverse events were associated with missing more than 3 doses per month and concomitant medication use.

Among those age 65 and older, none taking rifampicin had grade 3-4 hepatotoxicity, compared with 7 (6%) among those age 65 and older taking isoniazid.

“The main takeaway is that when rifampicin is not contraindicated due to concomitant medications or allergies, it should be a primary treatment option considered by clinicians and health care providers who prescribe latent tuberculosis treatment,” Campbell told Contagion^®. “Latent tuberculosis is completely asymptomatic, so safety should be the major consideration for providers and patients when deciding on treatment.”

Testing to rule out active tuberculosis could address fears of propagating rifampicin-resistance through monotherapy of active tuberculosis, the study noted, adding that there was no difference in drug resistance between the two groups and 1 case was noted in each group.

“The next steps for us are to take a look into patient and clinical factors associated with early discontinuation of treatment, which could help inform evidence-based interventions to help patients finish therapy,” Campbell told Contagion^®. “We're also currently finishing up some work looking at the costs associated with rifampicin treatment, which we hope to have published soon.”

The World Health Organization reported that more than 7 million people worldwide received treatment for tuberculosis in 2018, and the number of TB-related deaths feel from 1.6 million in 2017 to 1.5 million in 2018. The World Health Assembly set a goal of reducing TB deaths by 90% and incidences by 80% by 2030. Barriers include lack of funding, reaching at-risk children and drug resistance.

The risk of contracting TB is 16 to 27 times greater for people living with HIV, for whom TB is a major cause of mortality. The deadly combination of these disease had been the focus of research.