Short-course therapy takes a test flight

First projects target groups at highest risk

For a handful of TB control programs around the country, two months of therapy from start to finish sounds too enticing to pass up. At least three programs have already set up pilot programs using the new, short-course preventive therapy regimen.

The super-short regimen substitutes a combination of rifampin (RIF) and pyrazinamide (PZA) for the standard 12-month course of isoniazid (INH) monotherapy prescribed for HIV-infected patients. If given on a twice-weekly dosing schedule, the regimen can be trimmed to as few as 16 doses in all.

TB controllers in Florida, as well as San Francisco and Baltimore, say they're ready to try it out - but for starters, only on HIV-infected patients judged least likely to be able to finish the standard 12-month course of INH.

In San Francisco, TB controller Tony Paz's excitement is palpable. "Even among the hardest of the hard core, this two-month regimen seems doable," he says. "The possibilities are immense. Now, we have a real opportunity to do preventive therapy on folks who wouldn't stick with a six- or 12-month regimen."

In five years' worth of trials, the new regimen trounced the competition when it came to completion rates, and proved itself to be just as efficacious. Patients on the two-month regimen averaged completion rates of 80%, compared with those on a 12-month regimen of INH, who averaged 68%.

Even the toughest cases can finish 16 doses

San Francisco is opting for the twice-weekly, 16-dose variation of the regimen, which will be administered under direct observation, Paz says. "Even with the toughest cases of nonadherence, we have field staff who can latch onto these folks and make sure they pop their 16 doses," he says. "We'll use incentives and pay them if we need to; it's well worth it."

Although RIF and PZA are much more expensive than INH, most experts predict that savings on personnel costs will make the price of the drugs worthwhile. Plus, if more patients complete preventive therapy, that translates to fewer future cases, less transmission, and still more long-term savings, adds Paz.

As TB rates go down, experts are urging programs to do more preventive therapy, especially among high-risk groups. Recent reports from the 12th World AIDS Conference lent emphasis to the task, with one report showing that the annual rate of TB in the United States is 40 times higher among HIV-infected people than among the general population. (See related story p. 93.)

As we go to press, the Centers for Disease Control and Prevention (CDC) were expected to issue new guidelines in July for prophylaxis and treatment of co-infected patients. Meanwhile, CDC experts say, there's no reason not to go ahead with the new regimen - provided clinicians observe the appropriate precautions.

"Rifampin is a drug we don't want to mess around with," says Patty Simone, MD, chief of the Field Services Branch of the CDC's Division of TB Elimination. "One thing we need to do is make sure we screen really carefully for active disease."

So far, San Francisco is trying out the new regimen among two groups, says Paz: dually infected patients who are in jail and likely to stay there long enough to get 16 doses of medication and residents of selected homeless shelters.

Since rifampin is contraindicated in conjunction with protease inhibitors (PIs), the San Francisco projects have excluded patients taking PIs, says Masae Kawamura, MD, medical director for the city's TB control program. (For patients who are taking the drugs, CDC guidelines were expected to recommend that clinicians substitute rifabutin for rifampin.)

Eventual plans may call for the city to begin extending the short-course regimen to patients who are taking PIs, Kawamura adds. For now, Paz says, the idea is to gradually add other high-risk groups to the first two, including substance abusers and residents of flophouses and single-room-occupancy hotels.

At some point, the city will begin offering short-course preventive therapy to HIV-negative people, too. "There's no reason to think it won't work for them, too," Paz adds.

In Baltimore, IDUs will be first in line

Baltimore is trying out the new regimen in a couple of its long-standing programs for injecting drug users, or IDUs, says city TB controller William Coggin.

Plans call for offering short-course therapy to one group of IDUs who are part of a clinic study and to another group whose members are clients of a needle-exchange program, Coggin says. Clinic participants will receive daily PZA and RIF, which they will self-administer; and the van that delivers clean needles will provide direct observation of twice-weekly doses of the preventive medicines.

Coggin notes that it's important to remember rifampin increases the clearance of methadone - meaning that IDUs on methadone will need to have their doses increased to prevent withdrawal.

In Florida, TB controllers are still in the early stages of making plans for a pilot program, says David Ashkin, MD, medical director for the state's TB control program. "We have a pilot that's undergoing review now," he says. "I'm not known really for being especially all that cautious," he adds, "but until we see how well it works, we don't want to widely recommend this new regimen."

Ashkin's reservations stem from his reluctance to take any chances with rifampin, a potent weapon against TB few clinicians want to risk losing. Plus, given his clinical and professional interest in hepatitis C, Ashkin also frets about issues related to hepatotoxity. In accordance with what CDC is expected to say in its new guidelines, Ashkin says he'll substitute rifabutin for rifampin - partly because he's found it's easier on the liver, he says, and because using it avoids problems that arise in patients taking PIs.

That choice, however, leaves Ashkin with something else to worry about. When rifabutin is employed for Mycobacterium avium prophylaxis in AIDS patients, "we think we've found some rifampin monoresistance secondary to the introduction of rifabutin," he says. Yet another reason to worry about rifampin monoresistance, he adds: AIDS patients tend to malabsorb their drugs.

All told, Ashkin's not as unhappy about the new regimen as it might sound. "I'd be lying if I didn't say we're all excited about this," he says. "It raises the prospects for getting high-risk people through a course of preventive therapy."

Resistance levels should be limited

As far as Ashkin's worries about rifabutin, it shouldn't pose too much danger, says Rick O'Brien, MD, chief of the Research and Eval-uation Branch of the Division of TB Elimination. True, resistance "has been reported," he says, "but it's uncommon. The fact that you're giving the drug in combination with PZA makes resistance even less likely."

For TB programs that don't have a handle on cases, there's one hazard that does deserve some thought, adds Kamamura. "If there's a lot of transmission in the community, you may not be doing someone a favor by putting them on just two months' of preventive therapy and then sending them back into the community," she says. That problem, of course, doesn't apply to her city, she adds.

The CDC's new guidelines for preventive therapy were initially scheduled to have appeared in a section on preventive therapy in a July issue of the Morbidity and Mortality Weekly Report. The MMWR was to have included the guidelines in a section on preventive therapy as part of a larger set of guidelines devoted to the subject of the treatment of patients co-infected with HIV and TB.

The subject of preventive therapy should get aired more thoroughly when experts convene at the CDC sometime in September to consider the topic of screening and preventive therapy for TB. "We'll look critically at the results of recent studies that have been done," says O'Brien. "Out of that meeting - pretty quickly, we hope - will come an updated set of recommendations on preventive therapy," he adds