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U.S. Department of Health and Human Services

  

TB Notes Newsletter

No. 2, 2005

TB TRIALS CONSORTIUM UPDATE

Focus on Pharmacokinetic (PK) Studies

The purpose of the TB Trials Consortium (TBTC) is to conduct programmatically relevant research that expands treatment and prevention options for TB control worldwide. The CDC and 28 clinical sites across the United States, Canada, and abroad (Uganda, South Africa, Brazil, and Spain) share overall consortium leadership in the conduct of 1) studies to evaluate the safety and efficacy of new TB treatment regimens; 2) pharmacokinetic studies of TB and HIV medication interactions; 3) studies of nucleic acid amplification methodologies in the diagnosis and management of active TB; and 4) studies of treatment for latent TB infection.

Evaluating possible causes for lower effectiveness of TB treatment with once-weekly rifapentine and isoniazid: studies 22PK and 25PK.
Rifapentine (RPT) is a rifamycin derivative with a very long half-life that is suitable for use in once-weekly treatment regimens for TB. Early studies using a once-weekly RPT and isoniazid (INH) regimen (RPT dose = 600 mg) found the treatment to be less effective than standard daily or twice-weekly therapy with INH and rifampin (RIF) [1,2]. Some experts suggested that the dose of RPT may have been too low and that low RPT concentrations were to blame for the failures.

Study 22 was a randomized trial of once-weekly INH/RPT vs twice weekly INH/rifampin (RIF) in the continuation phase of therapy, and enrolled over 1000 patients [3]. Both HIV-infected and HIV-uninfected patients were enrolled in the trial. Enrollment was closed early to HIV seropositive patients because of a high rate of acquired rifampin resistant relapses occurring among HIV seropositive patients on the once-weekly INH/RPT treatment [4]. Overall rates of failure/relapse in HIV-negative patients were 9.2% with INH/RPT and 5.6% with INH/RIF. In patients without cavitary disease (a major risk factor for relapse), rates of failure or relapse were 2.9% and 2.5% respectively.

Study 22PK enrolled 133 of 1004 HIV-seronegative patients from the parent study and 33 of 71 HIV-seropositive patients from the parent study. Overall, 54% (40 of 74) of all patients with failure or relapse in the treatment trial were included in the PK study. The analysis found that failures or relapses in the RPT arm were associated with low INH concentrations and with rapid INH acetylator type (higher metabolism of INH which leads to lower levels than in slow acetylators). [5] These data suggest there is a substantive role for INH (the companion drug) in the continuation phase of once-weekly, RPT-based therapy.

Study 25 was a prospective, randomized, double-blind study comparing the tolerability of RPT doses of 600, 900, and 1,200 mg, all given with INH in the continuation phase of TB treatment among 150 patients. All dose sizes were generally well-tolerated and safe. There was a nonsignificant trend toward higher drug-related toxicity at RPT doses higher than 20 mg/kg. The study found that a 900-mg dose is generally safe and well-tolerated, and that the 1,200-mg dose warrants further evaluation. [6]

Study 25PK enrolled 35 of the 150 Study 25 patients. This PK sub-study found that higher RPT doses (600, 900, and 1,200 mg) directly correlated with increasing drug concentrations (measured as mean area-under-plasma-concentration time curve [mean AUC]; mean AUC was 296, 410, and 477 μg*h/ml at 600, 900, and 1,200 mg doses respectively). It also found that over half of patients had detectable RPT plasma concentrations for more than 36 hours after clearance of the concurrently administered INH. Higher RPT concentrations were achieved with greater doses, but clearance of INH did not match that of RPT. [7]

Taken together, these data support continued pursuit of RPT-based TB regimens, especially with a companion drug that will have a long half-life similar to RPT. The newer quinolone, moxifloxacin, is one such candidate (see Study 27 and 28 enrollment updates below). Study 25 results suggested that a higher dose of RPT could be used safely, and thus 900 mg of RPT was chosen for the large TBTC prevention trial (Study 26) that is currently underway.

Drug-drug interactions in concurrent treatments of HIV and TB: Study 23PK
On a worldwide basis, TB is one of the most common opportunistic infections among persons with HIV infection and is associated with a high rate of HIV disease progression. TB patients coinfected with HIV should thus be a high- priority population for anti-HIV treatment, or highly-active antiretroviral therapy (HAART). Drug-drug interactions between RIF, the key drug in short-course TB treatment, and protease inhibitors, one of the major classes of anti-HIV drugs, make concurrent treatment of TB and HIV difficult. Rifampin induces rapid metabolism of protease inhibitors, making them ineffective. Rifabutin is a rifamycin closely related to rifampin, with similar activity against M. tuberculosis in vitro and in clinical trials. Compared to rifampin, it is a less potent inducer of hepatic cytochrome P450 enzymes, and thus has less effect on the metabolism of protease inhibitors. Consequently it has been recommended for use in the treatment of HIV-TB when HAART Is to be administered concurrently.  However, there was relatively little published experience with rifabutin for treatment of HIV-related TB.

Study 23 evaluated HIV-infected patients with TB treated by DOT using a twice-weekly rifabutin-based regimen. The study was a single-arm trial designed to evaluate the safety and efficacy of rifabutin-containing short-course therapy for HIV-infected TB patients. Subjects were allowed to take antiretroviral therapy as prescribed by their HIV/AIDS care provider. During the first 2 months of TB treatment, the intensive phase, patients were treated with INH, PZA, and ethambutol, in addition to rifabutin. After 2 months of TB treatment, all patients were treated with twice-weekly rifabutin plus INH. The use of HAART and the timing of its initiation were at the discretion of the HIV care provider. Although the rate of treatment failure or relapse was not comparable (9/169 or 5%) to other treatment studies, 8 of the 9 patients with failure or relapses had acquired rifamycin resistance (ARR). All patients with ARR had advanced AIDS (CD4 cell count < 100). Because of this unexpectedly high rate of ARR, enrollment into the trial was stopped early. Twice weekly TB therapy is no longer recommended for patients with advanced AIDS (CD4 cell count < 100) [8].

Study 23A-PK included 102 of the 169 total patients enrolled in the parent study. This is the largest study to date of TB drug pharmacokinetics in HIV-infected patients and the first to study drug pharmacokinetics associated with acquired rifamycin resistance [9]. Low rifabutin concentrations and to a lesser extent low INH concentrations were associated with rifamycin-resistant treatment failure or relapse. Additionally, the concentrations of INH in the HIV-infected patients with TB were lower than those generally seen in HIV-uninfected TB patients [10]. Two other substudies examined interactions between rifabutin and nelfinavir or efavirenz.

Study 23B-PK: Data were collected from seven patients with HIV and TB started on nelfinavir-based HIV treatment during Study 23. This substudy measured RBT levels while on 300 INH/300 RBT biweekly before starting antiretrovirals, and then again after starting nelfinavir (1250 bid) plus two nucleosides, and while continuing the same TB drug dosing. The study found that nelfinavir levels were similar to those reported in previous studies of this dose and that rifabutin levels increased significantly after starting nelfinavir. The study concluded that dosing based on current guidelines does result in increased rifabutin levels but these levels were still within acceptable range for efficacy and safety [11].

Study 23C-PK: Data were collected from 15 patients with HIV and TB started on efavirenz-based HIV treatment during Study 23. This substudy measured RBT levels while on 300 INH/300 RBT biweekly before starting anti-HIV therapy, and then again after starting Efavirenz (600 mg qhs) plus two nucleosides, and while increasing the RBT dose to 600 RBT biweekly (in combination with the same dose of INH). The study demonstrated that a rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction, and that efavirenz levels were comparable to historical controls [12].

In summary, TBTC has been able to carry out pharmacokinetic studies associating TB drug levels with disease outcome and host conditions. Results to date have helped shape current treatment guidelines [13] and demonstrate the importance of incorporating pharmacokinetic evaluations into studies of new regimens to treat TB.

References

  1. Tam CM, Chan SL, Lam CW, et al. Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis: initial report. Am J Respir Crit Care Med 1998; 157: 1726–33.
  2. Anon. Package insert for rifapentine (Priftin®). Kansas City: Hoechst Marion Roussel, 1998.
  3. Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for the treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients. Lancet 2002;360:528-34.
  4. Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999;353:1843-47.
  5. Weiner M, Burman W, Vernon A, et al. Low INH concentrations and outcome of TB treatment with once-weekly INH and rifapentine. Am J Respir Crit Care Med 2003;167:1341-1347.
  6. Bock NN, Sterling TR, Hamilton CD, Pachucki C, Wang YC, Conwell DS, Mosher A, Samuels M, and Vernon A, for the Tuberculosis Trials Consortium. A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment. Am J Respir Crit Care Med 2002; 165: 1526-30.
  7. Weiner M, Bock N, Peloquin CA, Burman WJ, Khan A, Vernon A, Zhao Z, Weis S, Sterling TR, Hayden K, and Goldberg S, for the Tuberculosis Trials Consortium. Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. Am J Respir Crit Care Med 2004; 169: 1176-7.
  8. CDC. Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens.  MMWR 2002;51:214-15.
  9. Weiner M, Benator D, Burman W, et al. The association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clinical Infectious Diseases 2005, in press.
  10. Weiner M, Burman W, Khan K, Peloquin CA, Benator D, Vernon A, Zhao Z, Weis S and the Tuberculosis Trials Consortium. The effect of HIV serostatus on isoniazid pharmacokinetics among patients with active tuberculosis. Am J Respir Crit Care Med 2004; 169: A260.
  11. Benator D, Weiner M, Burman W, et al. Intensive pharmacokinetics of the nelfinavir-rifabutin interaction in patients with HIV-related tuberculosis treated with a twice-weekly rifabutin-based regimen. Abstract 96, American Thoracic Society 100th International Conference, Orlando, Florida, 2004.
  12. Weiner M, Peloquin C, Khan A, Vernon A, Engle M, Benator D, Fitzgerald M, Zhao Z, Burman B and the Tuberculosis Trials Consortium. Intermittent rifabutin and isoniazid with daily efavirenz in combination with two nucleosides for treatment of HIV infection and tuberculosis disease.  11th Conference on Retroviruses and Opportunistic Infections (Poster #761), Program Abstracts, page 350. Online at http://www.retroconference.org/2004/AbstractSearch/AbstractSearch.aspx 
  13. American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167(4):603-62.

Study enrollment updates:

Study 24 a single-arm study of largely intermittent, short-course therapy for patients with INH-resistant TB or INH intolerance. Enrollment closed December 2004 with a total of 98 patients. By mid 2007, all patients will have reached the end of follow-up for study outcomes (treatment failure and relapse).

Study 26 is a trial of short-course treatment of latent TB infection among contacts of active cases, using a 3-month once-weekly regimen of isoniazid 900 mg and rifapentine 900 mg, compared to standard 9-month therapy with isoniazid 300 mg. As of May 12, 2005, Study 26 enrollment is up to 4,485, well over half of the goal of 7,700 subjects for total enrollment.

Study 27 is a double-blind, placebo-controlled comparison of the efficacy and tolerability of moxifloxacin versus ethambutol in the initiation phase of treatment of pulmonary TB. Enrollment began in July 2003 at North America TBTC sites, in September 2003 at the Kampala, Uganda, site and in July 2004 at the Durban, South Africa, site. The enrollment goal was recently increased from 300 to 330 patients in order to ensure sufficient data for evaluation. Enrollment was completed in March 2005, with a total of 337 patients. Results will be presented in May 2005.  

Study 28, evaluation of a moxifloxacin-based, isoniazid-sparing regimen for TB treatment. The main comparison in Study 28 involves moxifloxacin with isoniazid (rather than with ethambutol). Data from the murine model of tuberculosis influenced this trial design; in the murine model the substitution of moxifloxacin for isoniazid resulted in significant reductions in the time to culture conversion and the time to sterilization when compared to the standard combination of rifampin, isoniazid, and pyrazinamide. This Phase II clinical trial will compare the safety and activity of a moxifloxacin-containing regimen (moxifloxacin, rifampin, pyrazinamide, ethambutol) in which moxifloxacin has been substituted for isoniazid, to the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol) in the first 2 months of treatment of sputum smear-positive pulmonary TB. Improved sputum culture conversion after 2 months of treatment with a moxifloxacin-containing regimen would support phase 3 clinical trials of moxifloxacin-based treatment regimens of less than the current 6-month standard regimens. The plan is to enroll 410 patients from both domestic and international TBTC sites. Enrollment is expected to begin by May 2005.

Submitted by Susan M. Ray, MD
Emory Univ. School of Medicine
Member, Advocacy & External Relations Committee. TBTC

 


Released October 2008
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