BOSTON – Current daily doses of rifampin for treating pulmonary tuberculosis may be too low and could be safely increased, results of a randomized phase 2 study suggest.

“Back in the 1970s, rifampin was an expensive drug, and attempts to shorten TB therapy using higher but intermittent doses of rifampin were unsuccessful at that time because of increased toxicity. That line of inquiry was essentially dormant for 40 years,” said Gustavo Velásquez, MD, from Brigham & Women’s Hospital in Boston.

More recent controlled trials have evaluated higher daily doses of rifampin, but none thus far have looked at concentration-dependent drug activity in Latin American patients or at efficacy as a function of the parameter that is thought to best predict rifampin activity, which is the ratio of the area under the curve to the maximum inhibitory concentration (AUC/MIC) of rifampin, he said at the Conference on Retroviruses and Opportunistic Infections.

To get a better idea of optimal rifampin dosing for the treatment of pulmonary TB, Dr. Velásquez and his colleagues conducted the HIRIF (High-Dose Rifampin in Patients With TB) trial. The phase 2 study was designed to evaluate the pharmacokinetics, efficacy, and safety of higher daily rifampin doses for pulmonary TB.

They looked at the three parameters across three treatments arms: 10 mg/kg rifampin (the current standard of care), 15 mg/kg, or 20 mg/kg.

Patients in Peru were screened, enrolled, and randomized in cohorts of 60 patients each to one of the three specified dose levels, which they received either as additional rifampin tablets or placebo for the first 8 weeks of treatment, after which all patients were continued on rifampin 10 mg/kg to complete a 6-month regimen. All patients were followed for an additional 6 months to for assessment of TB recurrence.

Rifampin total doses ranged from as low as 300 mg for patients in the 30 kg-37 kg weight range, to as high as 1,500 mg for those weighing more than 70 kg.

The efficacy analysis was by modified intention to treat, excluding 6 patients who had insufficient log₁₀ colony-forming units (CFUs) of TB, and a per-protocol analysis excluding an additional 42 patients whose doses of rifampin were affected by three study halts for adverse events. After each halt and review by the data-safety monitoring board, the trial was allowed to resume, but because enrollment and experimental dosing also were suspended, patients in the 15- and 20-mg/kg arms received 10 mg/kg during the 2-5 week halts. The number of patients in the 10-, 15-, and 20-mg/kg doses included in the per-protocol analysis were 56, 38, and 38, respectively,

Pharmacokinetic evidence from this study, previously published, showed that the median maximum drug concentration (C_max) in serum in the experimental arms reached the lower end of the targeted range of 8 mcg/mL or greater, whereas the median in the standard-of-care arm was 6.2 mcg/mL. Only 33% of patients in the 10-mg/kg arm reached the minimum 8-mcg/mL level, Dr. Velásquez noted, vs. 72% and 81% of patients in the 15- and 20-mg/kg doses, respectively.

In the modified intention-to-treat population, for every 5-mg/kg increase in rifampin dose, there was a nonsignificant trend toward faster decline in TB CFUs in sputum. Similarly, for every 1-log increase in rifampin AUC/MIC, there was a trend, albeit nonsignificant, toward faster decline.

However, in patients in the per-protocol analysis, every 5-mg/kg dose increase and 1-log increase in rifampin AUC was associated with significantly faster declines in CFUs (P = .022 and .011, respectively).

An analysis of treatment outcomes at 12 months, a secondary endpoint, showed that there were five cases of treatment failure, including three in the control arm and one each in 15- and 20-mg/kg arms, and six cases of recurrence after cure, which occurred in three, one, and two patients, respectively,

The safety analysis by intention-to-treat showed that the incidence of grade 2 or greater rifampin-related adverse events (AEs) were 43.3%, 51.7%, and 38.3% in the 10-, 15-, and 20-mg/kg doses, differences that were not statistically significant.

In addition, there were no significant differences among the treatment arms in either time to first grade 2 or greater rifampin-related AEs, the occurrence of one or more grade 2 or greater hepatic rifampin-AEs, or time to first hepatic rifampin-related AEs of grade 2 or above.

Dr. Velásquez noted that the study was limited by the possibility that the study halts could have biased efficacy effect estimates toward null and by differences in weight distribution among the three treatment arms.

“This actually is the first trial that shows not only a dose response of rifampin but also an exposure response of rifampin in combination therapy,” he said. “Our study supports that even higher doses of rifampin beyond what we studied of 20 mg/kg should be studied for potential treatment shortening.” The evidence also suggests that the current 10-mg/kg dose is low and could be safely increased to a 15- or 20-mg/kg dose, he concluded.

In a media briefing following the presentation, moderator Constance Benson, MD, from the University of California San Diego, who was not involved in the study, commented that with “high-dose rifampin, I think we have a really very robust body of literature to which this study can be added, demonstrating the safety of high-dose rifampin in the context of TB treatment.”

“There are some circumstances where I think using a much higher dose than we’ve been using would be an appropriate thing to do,” she added.

Examples of patients who might benefit include patients with disseminated TB or people with more serious TB than the average case, she said.

The study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Velásquez and Dr. Benson reported no relevant conflicts of interest.

SOURCE: Velásquez GE et al. CROI 2018, Abstract 39LB.

Are higher rifampin doses for pulmonary TB more effective?