December 7, 2011 — Weekly rifapentine plus isoniazid given under direct supervision for 3 months was as effective in preventing tuberculosis (TB) as 9 months of daily self-administered isoniazid, according to a report published in the December 8 issue of the New England Journal of Medicine.
During the 33 months after therapy, 7 of 3986 high-risk adult participants (0.19%) in the combination rifapentine-isoniazid treatment group developed culture-confirmed TB compared with 15 of 3745 (0.43%) patients who only received isoniazid (P < .001) in an open-label, randomized, noninferiority trial.
Mycobacterium tuberculosis, the slow-dividing bacterial pathogen that causes TB, poses a public health challenge because it can reside asymptomatically in a host's lungs for years before progressing into active disease. One third of the world's population is thought to be infected with TB, with 9.4 million new cases and 1.3 TB-related deaths worldwide each year.
From a practical standpoint, TB's lack of symptoms in its latent stage, combined with the complexity of standard therapy, make it difficult to treat. The current standard regimen is 9 months of daily isoniazid.
The drug is considered to be from 69% to 93% efficacious for HIV-negative patients who complete the 9-month treatment cycle. However, it is less effective in regular practice because only 30% to 64% of patients complete the drug regime.
Therefore, Timothy R. Sterling, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, and international collaborators in the PREVENT TB Study Team tested whether the 3-month regimen of rifapentine (900 mg) plus isoniazid (900 mg) would be as effective as 9 months of daily self-administered isoniazid (300 mg) alone in preventing TB.
The trial results suggest that the combination is as effective as standard therapy and improves therapeutic completion rates. Of the patients who received combination therapy, 82.1% completed the treatment regime compared with 69.0% of those prescribed standard isoniazid therapy.
When the investigators examined culture-confirmed TB rates in the subset of patients who completed treatment, there was no difference between the 2 treatment groups, with 5 of 3376 patients (0.1%) in the combination therapy group and 6 of 2792 patients (0.2%) in the isoniazid-only group developing TB.
More patients in the combination therapy group permanently discontinued treatment because of an adverse event than patients in the isoniazid group (P = .009). However, the overall adverse event rate and the severity of adverse rates were actually higher among patients who received isoniazid therapy, Dr. Sterling and colleagues report. This apparently contradictory finding may stem from the combination therapy group's greater contact with medical personnel during the trial, the authors explain.
The researchers found that 2.7% of the patients in the isoniazid treatment group discontinued therapy because of hepatoxicity compared with 0.4% of patients in the combination therapy group.
In an accompanying editorial, Christopher Dye, FMedSci, director of TB Health Information at the World Health Organization, noted that whereas the shorter regimen appeared effective in the low-incidence countries that participated in the current trial, preventive therapy has the potential to provide even greater health benefits in countries with a high incidence of TB.
"In this context, a critical question for the isoniazid-plus-rifapentine regimen is whether 3 months of treatment will provide protection for longer than 2 to 3 years," he writes. Moreover, further studies are needed to determine how this regimen compares with 4 months of rifampin monotherapy, which is used in communities with high AIDS and HIV incidence in which isoniazid use is not recommended.
The study is limited because the noninferiority margin (0.75%) was high compared with the event rate in the 2 study groups. In addition, the low HIV infection rates among patients precluded an opportunity to evaluate the disease's effect on the 2 treatment regimes. Children and adolescents were excluded from the trial.
Dr. Sterling received research grant funding from Bristol-Myers Squibb and Pfizer for HIV observational studies. One coauthor each has received research funding from sanofi-aventis and Ostuska America Pharmaceuticals. Dr. Dye has disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2155-2166.
During the 33 months after therapy, 7 of 3986 high-risk adult participants (0.19%) in the combination rifapentine-isoniazid treatment group developed culture-confirmed TB compared with 15 of 3745 (0.43%) patients who only received isoniazid (P < .001) in an open-label, randomized, noninferiority trial.
Mycobacterium tuberculosis, the slow-dividing bacterial pathogen that causes TB, poses a public health challenge because it can reside asymptomatically in a host's lungs for years before progressing into active disease. One third of the world's population is thought to be infected with TB, with 9.4 million new cases and 1.3 TB-related deaths worldwide each year.
From a practical standpoint, TB's lack of symptoms in its latent stage, combined with the complexity of standard therapy, make it difficult to treat. The current standard regimen is 9 months of daily isoniazid.
The drug is considered to be from 69% to 93% efficacious for HIV-negative patients who complete the 9-month treatment cycle. However, it is less effective in regular practice because only 30% to 64% of patients complete the drug regime.
Therefore, Timothy R. Sterling, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, and international collaborators in the PREVENT TB Study Team tested whether the 3-month regimen of rifapentine (900 mg) plus isoniazid (900 mg) would be as effective as 9 months of daily self-administered isoniazid (300 mg) alone in preventing TB.
The trial results suggest that the combination is as effective as standard therapy and improves therapeutic completion rates. Of the patients who received combination therapy, 82.1% completed the treatment regime compared with 69.0% of those prescribed standard isoniazid therapy.
When the investigators examined culture-confirmed TB rates in the subset of patients who completed treatment, there was no difference between the 2 treatment groups, with 5 of 3376 patients (0.1%) in the combination therapy group and 6 of 2792 patients (0.2%) in the isoniazid-only group developing TB.
More patients in the combination therapy group permanently discontinued treatment because of an adverse event than patients in the isoniazid group (P = .009). However, the overall adverse event rate and the severity of adverse rates were actually higher among patients who received isoniazid therapy, Dr. Sterling and colleagues report. This apparently contradictory finding may stem from the combination therapy group's greater contact with medical personnel during the trial, the authors explain.
The researchers found that 2.7% of the patients in the isoniazid treatment group discontinued therapy because of hepatoxicity compared with 0.4% of patients in the combination therapy group.
In an accompanying editorial, Christopher Dye, FMedSci, director of TB Health Information at the World Health Organization, noted that whereas the shorter regimen appeared effective in the low-incidence countries that participated in the current trial, preventive therapy has the potential to provide even greater health benefits in countries with a high incidence of TB.
"In this context, a critical question for the isoniazid-plus-rifapentine regimen is whether 3 months of treatment will provide protection for longer than 2 to 3 years," he writes. Moreover, further studies are needed to determine how this regimen compares with 4 months of rifampin monotherapy, which is used in communities with high AIDS and HIV incidence in which isoniazid use is not recommended.
The study is limited because the noninferiority margin (0.75%) was high compared with the event rate in the 2 study groups. In addition, the low HIV infection rates among patients precluded an opportunity to evaluate the disease's effect on the 2 treatment regimes. Children and adolescents were excluded from the trial.
Dr. Sterling received research grant funding from Bristol-Myers Squibb and Pfizer for HIV observational studies. One coauthor each has received research funding from sanofi-aventis and Ostuska America Pharmaceuticals. Dr. Dye has disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2155-2166.
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