Rifampin Promising for Latent TB in Phase 3 Trials

Marcia Frellick

August 01, 2018

Treating children and adults who have latent tuberculosis infection (LTBI) with 4 months of rifampin (Rifadin, Sanofi-Aventis) had similar rates of safety and efficacy but a better adherence rate than 9 months of treatment with the standard isoniazid, also known as isonicotinoylhydrazine (INH), two large, phase 3, randomized controlled studies indicate.

Rifampin also has the advantage of being a one-drug regimen with existing palatable formulations for children, one of the studies notes.

The findings of the two multicenter, open-label trials are important, as the 9-month regimen of isoniazid has been linked to poor adherence rates and toxic effects in children and adults. Researchers note that an estimated one quarter of the world's population has LTBI.

Results of both studies were published online August 1 in the New England Journal of Medicine.

National TB expert Kevin Winthrop, MD, MPH, from Oregon Health & Science University's School of Public Health in Portland, who was not involved with the trials, told Medscape Medical News the results confirm what many already believe and have put into practice: the shorter regimen should be preferred.

Winthrop, a former staff member in the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention, Atlanta, Georgia, said physicians have been awaiting these results to confirm the shorter regimen is better after seeing promising results in phase 2 trials.

"This is the definitive trial," he said. "The holy grail on the treatment side is, 'Can we shorten therapy for both active and latent TB?' The shorter it goes, the easier it is for patients to complete their therapy."

Adult Study Conducted in Multiple Countries

In the study of adults, Dick Menzies, MD, from the Respiratory Epidemiology and Clinical Research Unit at Montreal Chest Institute at McGill University Health Centre Research Institute, Quebec, Canada, and colleagues randomly assigned adults with LTBI to treatment with 4 months of rifampin or 9 months of isoniazid for the prevention of active TB within 28 months of randomization.

The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid and had a higher rate of treatment completion and better safety.

Among 3443 patients who received rifampin, four developed confirmed active TB and four developed clinically diagnosed active TB during 7732 person-years of follow-up compared with four and five patients, respectively, among 3416 of those in the isoniazid group during 7652 person-years of follow-up.

The rate differences (rifampin minus isoniazid) were fewer than 0.01 cases per 100 person-years (95% confidence interval [CI], −0.14 to 0.16) for confirmed active TB and fewer than 0.01 cases per 100 person-years (95% CI, −0.23 to 0.22) for confirmed or clinically diagnosed TB, the researchers write.

The upper ends of the 95% confidence intervals for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of TB were less than the targeted noninferiority margin of 0.75 percentage points in cumulative incidence, and the rifampin regimen was not superior to the isoniazid treatment.

However, completion rates for the rifampin regimen were 15.1 percentage points higher (95% CI, 12.7 - 17.4). The rate differences for adverse events grades 3 to 5 that occurred over the course of 146 days were −1.1 percentage points (95% CI, −1.9 to −0.4) for all events and −1.2 percentage points (95% CI, −1.7 to −0.7) for hepatotoxic events.

The trial was conducted in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea.

Better Completion Rates Also Seen in Children

The trial conducted in children showed similar results.

Thierno Diallo, MD, from ôpital National Ignace Deen, Université Gamal Abdel Nasser de Conakry in Guinea and the Montreal Chest Institute at McGill University Health Centre Research Institute, and colleagues randomly assigned 844 children younger than 18 years who had LTBI to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was grade 1 to 5 adverse events that resulted in a trial drug being stopped permanently. Secondary outcomes included efficacy, adverse effects, and treatment adherence.

Of the 422 children in the rifampin group, 360 (85.3%) completed per protocol therapy compared with 311 (76.4%) of 407 children in the INH group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% CI, 7.5 - 19.3 percentage points).

There were no grades 1 through 5 adverse events attributed to either drug. Active TB, including one isoniazid-resistant case, was diagnosed in two children in the INH group during 542 person-years of follow-up, and in no cases in the rifampin group during 562 person-years (rate difference, −0.37 cases per 100 person-years; 95% CI, −0.88 to 0.14).

Some Have Already Changed to the 4-Month Regimen

Winthrop, who is also the TB consultant for the Oregon Health Authority, said the state had already switched to the shorter regimen.

"We instructed the counties and the local health departments here that we preferred 4 months [of] rifampin. That's our preferred regimen, and it has been for several years," he said.

He praised the work of the research teams. "It's a well-designed trial and proves everything we thought from the last few studies," he said.

Rifampin May Not Be Best for All Patients

However, rifampin may not be the best choice for all patients, Winthrop said, and in some cases, 9 months of INH is a good alternative. Rifampin can interact with several other medications, and some people who are receiving a number of medications may not be best suited for rifampin, he explained.

For example, rifampin will make certain blood pressure medications ineffective, he said. "Rifampin basically revs up some of the enzymes in your liver, and those enzymes then chew through other medicines and degrade them more quickly."

"When I have someone on certain blood pressure pills, particularly someone with hard-to-control hypertension, rifampin may not be a good choice for them," Winthrop said. "There are things you can do if they are on rifampin: you can increase their blood pressure pill dosage to try to overcome that interaction, and that's what we usually do."

Rifampin also can make some blood thinners ineffective, he said, and in specialized cases, patients may be better off with INH.

But he says those cases are the exception, and he "very rarely" in his own practice prescribes 9 months of INH.

"We're drifting toward shorter regimens that are rifampin-based," Winthrop said. "Proving that they are safer and at least as effective as our prior gold standard, which was 9 months of INH, is really important, and these two studies do that."

The study of adults by Menzies et al was supported by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. The study of children by Diallo et al was supported by the Canadian Institutes of Health Research and the Conselho Nacional de Pesquisa in Brazil. The authors and Winthrop have disclosed no relevant financial relationships.

N Engl J Med. Published online August 1, 2018.

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