Fixed-dose combinations get a boost from WHO
Move should cut down on dosing errors
The concept of fixed-dose combination therapy (FDCT), a sometime ugly duckling in the world of directly observed therapy (DOT), got a makeover recently when the World Health Organization gave it a thumbs-up, commending it especially to health ministries in developing countries. TB experts in the United States are divided in their reaction to the change.
The policy change was announced recently by Sergio Spinaci, MD, a TB expert at WHO who currently serves as executive secretary of macroeconomics and health at the organization. Combination regimens are now both cheaper and more readily available, Spinaci pointed out, and their use should help cut down on dosing errors as well as supply problems, he said.
Historically, support for FDCT both here and abroad has been tepid, partly because of fears that fixed-dose regimens might undercut the motivation for implementing DOT because one of the main goals of direct observation is to make sure patients take all their pills, not just some of them.
The most positive effect of the new policy is that it will prevent patients "from picking and choosing" from among their medications, says Jim Yong Kim, MD, PhD, executive director of the Boston-based nonprofit organization Partners in Health. "This way, you can’t take out the rifampin and sell it on the black market for [treatment of] STDs," he says, citing one not-uncommon scenario.
Kim dismisses concerns that FDCT will crowd out DOT. "No one wants to see it replace DOT," he says. "The idea is to make DOT easier."
Even though common sense suggests that packaging separate components of a regimen into the same pill should decrease the likelihood of resistance, that’s technically an untested assumption, Kim and others note. No trial has ever directly compared FDCT to other dosing methods, says Rick O’Brien, MD, chief of the Research and Evaluation Branch of the Division for TB Elimination at the Centers for Disease Control and Prevention. Still, there is evidence to suggest the optimists are right about FDCT, he adds. The nation of Brazil, for one, has steadfastly resisted implementing DOT, uses FDCT, and boasts of notably low rates of drug resistance.
On the other hand, if FDCT is used in a setting where resistance already has a foothold, there could be trouble, says Tom Moulding, MD, professor of clinical medicine at Harper/UCLA Medical Center in Torrance, CA. That’s because ethambutol and pyrazinamide don’t work as well as rifampin and isoniazid, he explains. If one of those so-called "twin pillars" already isn’t working and a patient with mono-resistance who self-administers medications begins to skip doses, the result could be treatment failure and more drug resistance, Moulding warns.
FDCT reduces drug distribution costs
On the plus side, in developing countries where distribution systems are unreliable, implementing FDCT will assure that clinics get all the TB drugs they need, not just some of them, points out Moulding. It should keep costs down, too, he adds: "If you’ve got three drugs coming from three different companies, the amount of work you’ve got to do to make sure they all get there will be cut by using FDCT. Distribution systems are where you incur a lot of the cost."
The cost of the pills themselves has begun to come down, adds Kim. "Manufacturers in India are beginning to work on [FDCT], and soon we should see begin to get very low," he says.
Kim claims that the use of FDCT won’t result in TB patients taking fewer pills, because doses need to be adjusted according to a range of body weights, Kim adds. "So the number of pills people take will probably be about the same," he says. It’s also unlikely that FDCT will ever be used for treating multidrug-resistant TB, he says. "People have actually raised such a possibility, but I doubt it will happen," he says. "With treatment for MDR-TB, you have so many side effects that you want to retain flexibility."
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