Fixed-dose drug combos for TB are not better than separate formulations

“It was widely believed that FDC would reduce drug resistance development and improve adherence to treatment. In fact, neither was true — in 15 different randomized controlled trials. There is no need to use FDCs,” said senior investigator Dr. Dick Menzies of the Montreal Chest Institute at McGill University in Montreal, Canada, in an email to Reuters Health.

Coauthor Dr. Benjamin M. Smith, also of the Montreal Chest Institute, said in an email, “Compared with standard ‘loose pill’ regimens, fixed-dose combination therapy was associated with a trend toward higher rate of treatment. There is no need to use FDCs. We need a different solution.”

The authors’ literature search yielded 2,450 citations. They chose 25 articles reporting results from 19 trials that met their inclusion criteria. From these, they chose 15 randomized controlled trials (RCT) that directly compared FDC to separate drug formulations in a total of 5,630 patients. They analyzed the four cohort studies separately.

As reported online January 11 in ERJ Express, none of the 15 trials showed differences in acquired drug resistance, bacterial conversion after two months of treatment, or adverse drug reactions with FDC or separate drug formulations. A trend toward a higher risk of failure or relapse was seen with FDC (pooled RR, 1.28). The incidence of relapse or failure was low in both treatment arms; the pooled risk difference was 1% higher with FDCs.

Only one of the two trials that evaluated treatment satisfaction — and none of five that evaluated patient adherence — favored FDCs.

The four cohort studies included 2,672 patients. One comparative cohort had the highest proportion of “treatment failure or disease relapse,” ranging from 5% to 11% among drug-susceptible patients and from 21% to 35% among drug-resistant patients. The crude RR comparing FDC to separate formulations was 0.46 among drug-susceptible and 0.6 among drug-resistant patients.

The non-comparative cohort studies showed low rates of “treatment failure or disease relapse” (from 0.5% to 2%) and acquired drug resistance (from 0% to 0.3%) among patients treated for TB.

Dr. Smith observed, “The lack of benefit from fixed dose combination therapy for active tuberculosis is somewhat surprising. Successful treatment of active tuberculosis requires patient adherence to an appropriately prescribed regimen of several pills over several months. It was hoped that a fixed-dose combination regimen would simplify prescribing, reduce pill burden, and prevent inappropriate use of monotherapy.”

“Because clinical trials are often performed under ‘optimal’ conditions, with close follow-up and additional surveillance), the potential benefit of fixed dose therapy over ‘loose pills’ may have been obscured,” he added. “A pragmatic clinical trial, in which care is provided in a way that more closely resembles ‘real world’ practice, would help address this concern.”

Dr. Elizabeth Tam, of the John A. Burns School of Medicine at the University of Hawai`i at Manoa in Honolulu, said in an email that, “whether the dose is fixed appears less important than other measures that assure adherence (for example, directly observed therapy), and that assure appropriate choice of medications (for example, test the susceptibility of the strain and select accordingly). We need consistent definitions of adherence to improve future studies.”

She added, “As we move to high-value cost-conscious care, it would have been helpful to know the comparative costs of FDC vs standard therapy — not just the medications or formulations, but also the costs of administering, monitoring for side effects, dealing with side effects, etc.”

“So, particularly if FDC is roughly comparable to standard therapy in the primary and secondary outcomes pre-selected for this meta-analysis, if the cost of treatment is decreased by, say, 10-20%, that may change the conversation!”

TB infects about 8.7 million people worldwide each year and kills about 1.4 million. Inappropriate therapy and non-adherence to treatment regimens are thought to contribute significantly to this global public health problem.

The drugs involved in these studies included isoniazid, rifampicin, pyrazinamide, streptomycin, and ethambutol.

The authors and Dr. Tam reported no conflicts of interest with this study.

SOURCE: http://bit.ly/WBepld

Eur Respir J Express 2013.

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