DENVER – Shorter combination therapy was at least as efficacious as conventional longer monotherapy for preventing tuberculosis in patients with latent infection, according to final results of the phase III PREVENT TB trial.
The trial, also known as TB Trials Consortium Study 26, was conducted among more than 8,000 patients with latent TB infection who were at high risk for progression.
Dr. Timothy R. Sterling
After 33 months, the cumulative rate of TB disease was 0.19% in the group given 3 months of weekly rifapentine plus isoniazid under direct observation (3HP), compared with 0.43% in the group given 9 months of daily isoniazid on a self-administered basis (9H).
The difference between groups was well within the trial’s boundary set for noninferiority, lead investigator Dr. Timothy R. Sterling reported at an international conference of the American Thoracic Society.
In addition, although patients in the group given the shorter combination therapy were more likely to stop treatment specifically because of adverse events, they were still far more likely to complete treatment.
Taken together, the trial’s findings suggest that "3HP is an alternative to 9H for treatment of latent [TB] infection in persons at high risk for progression to tuberculosis," he said.
"3HP was as effective as 9H in this clinical trial, but in operational settings, 3HP could be more effective than 9H, particularly if 3HP is given under direct observation and 9H has completion rates of approximately 30%-60%," Dr. Sterling further noted. "And, with greater effectiveness, there would be more tuberculosis prevented."
The trial enrolled 8,053 patients older than 2 years of age from the United States, Canada, Brazil, and Spain who had a positive tuberculin skin test (or alternately, in the case of young children, close contact with someone with TB), plus factors putting them at high risk for progression.
The patients were randomly assigned in nearly equal numbers to two groups treated on an open-label basis.
The 3HP group was given once-weekly, directly observed treatment with rifapentine (brand name Priftin; 900 mg) plus isoniazid (brand name Nydrazid, also known as isonicotinic acid hydrazide or INH; 15-25 mg/kg) for 3 months. The 9H group was given daily self-administered isoniazid (5-15 mg/kg) for 9 months.
All patients also received vitamin B6. They were followed up for 33 months from the time of enrollment.
The patients had a median age of 37 years and 58% were white, reported Dr. Sterling, who is a professor of medicine and director of epidemiology research in the division of infectious diseases at the Vanderbilt Institute for Global Health in Nashville, Tenn. Overall, 3% were HIV positive.
In modified intention-to-treat analyses, the cumulative rate of culture-confirmed TB was 0.19% in the rifapentine plus isoniazid group, compared with 0.43% in the isoniazid-only group. The upper bound of the 95% confidence interval for the difference between these rates was 0.01% – far below the trial’s predefined noninferiority margin of 0.75%.
In per-protocol analyses, the cumulative rates were 0.13% and 0.32%, respectively. The upper bound of the 95% confidence interval for the difference between these rates was 0.06%, again well below the noninferiority margin.
In additional findings, compared with the 9H isoniazid-only regimen, the 3HP rifapentine plus isoniazid regimen was associated with a higher treatment completion rate (82% vs. 69%) and a lower rate of hepatotoxicity caused by the drug(s) (0.5% vs. 2.7%).
However, the 3HP regimen was also associated with higher rates of any adverse event attributable to the drug(s) (8.1% vs. 5.5%) and of permanent drug discontinuation because of adverse events (4.7% vs. 3.6%). These findings might have been caused by the decreased tolerability of the combination regimen, Dr. Sterling speculated, or to this group’s more frequent contact with study personnel or the trial’s open-label design with a novel regimen.
Neither rates of grade 3 and 4 toxicity nor rates of death differed significantly between groups, he noted.
The Centers for Disease Control and Prevention and the American Thoracic Society will be updating their TB recommendations when the data are published, according to Dr. Sterling.
"Uptake of the [3HP] regimen will depend on availability of rifapentine; but the manufacturer, Sanofi-Aventis, is committed to this," he added.
It will be important for TB treatment programs to be able to monitor for adverse events, Dr. Sterling, cautioned, given that previous experience suggests some TB regimens have poorer tolerability when used in the general population than when used in a clinical trial.
The shorter, more potent TB treatment regimen might improve patient adherence, said Dr. Kenneth Castro, director of the Division of TB Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), at the Centers for Disease Control and Prevention.