Rifapentine's impact may be great, but caution urged in its use

Drug could make greatest impact on preventive therapy

The Food and Drug Administration's approval of rifapentine last month gave clinicians the first new anti-tuberculosis drug in more than a decade, but TB experts are recommending caution and restraint in its use until more data accumulate on how it can be most effective.

"This drug has so much potential, but it has to be used correctly," says Lee Reichman, MD, director of the National TB Center in Newark, NJ.

"Correctly," at this juncture, is a more a matter of interpretation than hard science. The drug was approved on the basis of limited data, primarily from a trial whose dosing design was less than optimal, say health officials from the Centers for Disease Control and Prevention (CDC).

Nonetheless, the approval marks a potential turning point in the way tuberculosis will be treated and prevented. With a half-life significantly longer than rifampin, rifapentine has the distinct advantage of being administered once or twice a week instead of daily. How that will impact adherence is not yet clear, but many experts believe that once some of the issues surrounding administration are cleared up, rifapentine should make TB preventive therapy and treatment considerably easier for patients.

The drug's manufacturer, Hoechst Marion Roussel of Kansas City, MO, expects to have the drug available in the United States in September. Not yet approved in other countries, the drug will be submitted for regulatory approval in Europe later this year. The company also has plans to market the drug in developing countries, says spokeswoman Julie O'Dell. Pricing for the drug is not yet available, she adds.

Rifapentine (Priftin) was approved on the basis of an open-label, prospective, randomized trial involving 722 patients treated for pulmonary TB. The study was divided into two phases based on dosing frequency. In the first phase, half the patients were randomized to receive rifapentine, isoniazid, pyrazinamide, and ethambutol for 60 days. The other half were given rifampin, isoniazid, pyrazinamide, and ethambutol for the same length of time. During this intensive phase, all drugs were administered daily except for rifapentine, which was given twice a week.

For the second phase of the trial, patients who received rifapentine continued to receive that drug plus isoniazid once weekly for up to 120 days. Patients who received rifampin continued to receive that drug and isoniazid twice weekly for up to 120 days. Study results show that 87% of patients in the rifapentine arm converted to culture negative, compared with 81% in the rifampin arm. During follow-up, 10% of patients on rifapentine relapsed, compared with 5% for the rifampin group.

Prescribing with DOT

Based on those results and those of several other trials, Reichman says his center will most likely start prescribing rifapentine during the four-month maintenance phase for patients who are smear-negative after the first two months of treatment and who are compliant with directly observed therapy (DOT).

Until the American Thoracic Society and the CDC issue guidelines, he urged caution in making sure rifapentine is used optimally. Calls to the center's hotline indicate that patients mistakenly believe that they can switch rifapentine for isoniazid and that treatment can be shortened.

"So far, I would never recommend it be used without DOT," he tells TB Monitor. "And I would use it only in patients who respond well in the first two months of treatment."

Because the drug is new, Reichman adds that he probably would want to follow-up on patients after three months to make sure they have no problems with the drug. According to the package insert, the most common adverse reactions in the study were hyperuricemia, neutropenia, and pyuria. Side effects, however, were relatively few, and, as Reichman points out, rifapentine is a fairly benign drug, similar to rifampin in its toxicity profile. As with rifampin, the drug is contraindicated for protease inhibitors.

Because of its good safety profile, rifapentine could provide an alternative regimen to traditional isoniazid preventive therapy. Animal studies suggest that combining rifapentine with isoniazid once weekly for three months could be highly effective in preventing disease, according to a recent editorial by Richard O'Brien, MD, in the American Journal of Respiratory and Critical Care Medicine.1

"We sorely need a regimen that will prevent TB," Reichman says, "and I suspect that rifapentine or rifapentine combined with isoniazid for a couple of months will be that regimen."

Reichman notes that preventive therapy that uses less isoniazid, or none at all, could improve compliance, since isoniazid is not a popular drug with patients. "The problem with isoniazid is that it has a reputation it doesn't deserve - people are afraid of it," he explains. "I get patients all the time saying, `My physician told me if I have a drink I will die of hepatitis.'"

As chairman of the Tuberculosis Trials Con-sortium's external affairs committee, which conducted rifapentine Study 22, Reichman said he would push hard for a comparative study that would evaluate rifapentine for preventive therapy.

More patients could benefit from DOT

By allowing for intermittent therapy for treating disease and possibly shorter therapy for prophylaxis, rifapentine will be a boost for DOT, spreading resources farther and allowing more patients to enroll in supervised therapy. Although patient compliance might improve even with unsupervised treatment, Reichman warns that taking pills once or twice a week may be actually harder for some patients than taking them daily.

"Intuitively, I would say that intermittent regimens without DOT are less effective than daily regimens without DOT," he says. "The problem is how does a patient remember to take medication twice weekly. Maybe a phone call will work, but these are some of the issues that will have to be addressed."

Reference

1. O'Brien R, Vernon A. New tuberculosis drug development: How can we do better? Amer J Resp and Crit Care Med 1998; 157:1,705-1,707.