NEW YORK (Reuters Health) – Outcomes among tuberculosis patients treated with a fixed-dose combination of four drugs are similar to those in patients treated with the same four drugs given separately, an international team reports in the Journal of the American Medical Association for April 13.
The researchers explain that fixed-dose combination therapy has been advocated as a way to prevent the emergence of drug resistance caused by inappropriate dosing. It also simplifies drug procurement and enhances compliance.
To test this approach with a four-drug regimen, Dr. Christian Lienhardt, with the World Health Organization in Geneva, Switzerland, and colleagues in the Study C Trial Group randomized 1585 adults with newly diagnosed TB to daily rifampicin, isoniazid, pyrazinamide, and ethambutol given in fixed-dose combination tablets or to the same drugs in separate formulations, during an initial 8-week intensive treatment phase. All patients then received 18 weeks of rifampicin and isoniazid in fixed-dose combination tablets 3 times weekly.
Every treatment dose was taken under supervision of a medical staff member, i.e., as directly observed therapy.
Favorable outcomes, defined as a negative culture result at 18 months after randomization, were documented on a per-protocol basis in 93.9% of patients in the fixed-dose group and 94.6% of those on the separate drug regimen, the investigators report. This result met the study’s “strict” definition of non-inferiority, namely, “a lower level of the 2-sided 90% CI for the difference in outcome of no less than -4%.”
Corresponding favorable outcome rates in a modified intention-to-treat analysis were 83.3% and 84.8%, and in a post-hoc ITT analysis they were 89.8% vs 91.0%. However, one of these ITT results did not meet the prespecified non-inferiority margin.
Nonetheless, Dr. Lienhardt and colleagues conclude, “The results do support the WHO recommendations for use of FDCs (fixed-dose combinations) because of the potential advantages associated with their administration compared with separate-drug formulations.” As they point out, this strategy reduces the number of pills taken daily from 9-16 to 3-4 during the intensive phase.
The authors note that uptake of fixed-dose combination drug regimens is hampered by concerns about efficacy and quality. “For efficient tuberculosis control worldwide, it is essential that quality-assured FDCs are made available.”