麻豆传媒

A shorter, 4-month course of rifampin was non-inferior to the standard 9-month regimen of isoniazid at preventing active tuberculosis (TB) among adults with latent TB infection, a phase III trial found.

Rate differences were less than 0.01 cases per 100 person-years for confirmed active TB (95% CI -0.14 to 0.16) and for confirmed or clinically diagnosed TB (95% CI -0.23 to 0.22), though rifampin was not superior to isoniazid, reported Dick Menzies, MD, of McGill University in Montreal, and colleagues.

However, the rifampin regimen had higher rates of treatment completion and a better safety profile, they wrote in the .

A found there were no significant between-group differences among children with latent TB infection in the rates of adverse events. Once again, rifampin had a better rate of adherence.

Latent TB in Adults

Menzies' group noted that a 6- or 9-month regimen of isoniazid is recommended by the World Health Organization (WHO) for the treatment of latent TB infection, but added that this benefit may be reduced due to poor rates of completion and hepatotoxic effects.

But observational studies showed both "superior rates of regimen completion" with a 4-month regimen of rifampin compared with 9 months of isoniazid, and a previous randomized trial found a lower incidence of grade 3 or 4 drug-related adverse events, lower costs, and a higher rate of treatment completion with the rifampin regimen versus isoniazid.

Researchers conducted a clinical trial in nine countries, where adults with latent TB were randomized to receive either a 4-month regimen of rifampin or a 9-month regimen of isoniazid for prevention of confirmed, active TB within 28 months following randomization, the authors said. Patients were followed up monthly during the first 2 months and at a minimum of every eight weeks after that. The minimum number of trial-related visits for the rifampin group was 11 and those in the isoniazid group was 12.

Overall, 6,012 adults were included in a modified intent-to-treat analysis, with 5,744 completing 28 months of follow-up after treatment. Average age of participants was 38, and around 40% were men. The authors noted that more than 70% of participants were close contacts of someone with TB and 854 of 6,012 participants lived with at least one other trial participant.

There were eight cases of confirmed active TB and nine cases of clinically diagnosed active TB during active follow-up in both the phase II and phase III trials. But in all analyses of the phase III data, the "upper boundary of the 95% confidence interval for the difference in rates of confirmed active tuberculosis or of confirmed or clinically diagnosed tuberculosis was less than the prespecified margin for non-inferiority," the authors wrote.

A secondary outcome, rate of completion, was significantly higher in the rifampin group vs the isoniazid group, as well (difference 15.1 percentage points, 95% CI 12.7-17.4).

Safety was based on estimated rate differences for adverse events during the first 146 days after randomization. The rifampin group experienced significantly lower rates of grades 3 to 5 adverse events than the isoniazid group. Drug-induced hepatitis was the most common grade 3 or 4 adverse event, and was also less frequent in the rifampin group.

The study had some limitations including its open-label design and the "low event rate of active tuberculosis in each group in the modified intention-to-treat analysis," the authors noted."

Latent TB in Children

Thierno Diallo, MD, of Université Gamal Abdel Nasser de Conakry in Conakry, Guinea, and colleagues, included 829 children with latent TB infection, ages 0 to 17, in the analysis -- 422 were randomized to rifampin and 407 to isoniazid. They were an average age of 10 years, and 36% were boys. Notably, 128 were age <5, and 79 were age <2.

They reported no events of grade 1 through 5 attributed to either trial drug. There was one death due to a traffic accident in the rifampin group and one pregnancy in the isoniazid group.

Rate of completion was significantly higher in the rifampin group (adjusted difference 13.4 percentage points, 95% CI 7.5-19.3). Efficacy was mostly comparable between the two groups, with active TB diagnosed in two children in the isoniazid group (including one with resistance to isoniazid) compared to none in the rifampin group.

Despite this, the authors said they could not conclude that 4 months of rifampin was superior or non-inferior to 9 months of isoniazid for prevention of active TB.

"The main limitation of the trial was its open-label design, which may introduce bias, particularly for the ascertainment of completion or adverse events," the authors noted.