medwireNews: A 2-month regimen of rifampicin at 20 mg/kg per day has a similar safety profile to the standard 4-month regimen of 10 mg/kg per day, making it a possible alternative tuberculosis preventive treatment (TPT) option, say researchers.
However, individuals on this regimen were less likely than their peers on the standard lower-dose, longer-duration rifampicin regimen to complete the course, the team points out; a finding that they were unable to explain.
“[R]educing the duration of TPT while maintaining its safety, tolerability, and efficacy would increase TPT uptake, particularly in low-income and middle-income countries, which have the highest burden of tuberculosis,” write Dick Menzies, from McGill University Health Centre in Montreal, Quebec, Canada, and colleagues in The Lancet Respiratory Medicine.
The team compared safety and completion rates among 1368 patients randomly assigned to receive oral rifampicin at one of three doses: 10 mg/kg for 4 months (standard regimen), 20 mg/kg for 2 months, or 30 mg/kg for 2 months. Dosing was based on patient weight with those in the two higher-dose groups taking up to four rifampicin capsules per day.
The study participants (57% women) were aged a median of 41 years and were treated in Canada, Indonesia, or Vietnam. They all had an indication for TPT according to World Health Organization (WHO) and country-specific guidelines, primarily close contact with someone with pulmonary tuberculosis, plus a positive tuberculin skin test or interferon-γ release assay.
Treatment was completed by 82% of 454 patients in the standard treatment group, 71% of 461 patients receiving the 20 mg/kg regimen, and by 65% of those receiving the 30 mg/kg regimen. The patients taking the 20 mg/kg and 30 mg/kg rifampicin doses were a significant 7.8% and 15.4% less likely to complete treatment than those receiving the standard dose.
The two most common reasons for noncompletion of treatment (fewer than 80% of intended doses) were patient choice to stop (16%) and adverse events (6%).
Among the 1303 participants who commenced treatment, protocol-defined adverse events of grade 3–4 or any-grade rash, allergy, or hypersensitivity that were possibly or probably related to the study drug occurred in a similar proportion of patients in the standard and 20 mg/kg treatment groups, at 3% and 2%. This equated to a nonsignificant risk difference adjusted for clustering of 0.5% that met noninferiority based on a margin of 4%.
By comparison, the rate was significantly higher among patients in the 30 kg/mg group, at 7%, corresponding to significant risk differences of 4.6% compared with the standard rifampicin dose and 5.1% compared with the 20 mg/kg dose.
None of the patients in the standard treatment group developed hepatotoxicity of grade 3 or worse, compared with one in the 20 mg/kg group and four in the 30 mg/kg group.
This increased risk for hepatotoxicity with a daily rifampicin dose of 30 mg/kg is consistent with findings from other trials, such as the TRUNCATE and TridoRe trials, the researchers point out.
Overall, 85 (7%) participants experienced adverse events that led to treatment cessation, and these were deemed possibly or probably related to the study drug in the majority (92%) of cases.
In an accompanying comment, Theresa Ryckman and Nicole Salazar-Austin, both from Johns Hopkins School of Medicine in Baltimore, Maryland, USA, remark that while the study findings are “a great step forward to understanding the safety of higher-dose rifampicin for tuberculosis prevention, data on efficacy and a better understanding of the lower completion rates with 2 months of 20 mg/kg daily rifampicin are needed to fully characterise the potential of this regimen.”
They also comment that while this regimen could be “a compelling alternative to 4 months of the standard dose if found to be efficacious,” further comparisons with existing WHO-recommended short regimens in terms of “efficacy, tolerability, and cost-effectiveness” are needed.
The efficacy outcome of the current trial, defined as incidence of tuberculosis disease in the 26 months after randomization, will be reported separately once ongoing follow-up is completed in December 2024.
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Lancet Respir Med 2024; doi:10.1016/S2213-2600(24)00076-6 Lancet Respir Med 2024; doi:10.1016/S2213-2600(24)00107-3