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U.S. Department of Health and Human Services

  

TB Notes 1, 2005

No. 1, 2005

Updates from the Clinical and Health Systems Research Branch

Why the TB Trials Consortium Needs Your Support

The year is 2024. You are called to the public health clinic to consult on a TB case; its disposition is remarkably speedy and successful. A middle-aged woman and her three children (aged 5 to 12) who recently emigrated from another country are brought in for evaluation. The woman’s husband was diagnosed with TB the week before, when he presented to a local hospital with cough, fever, and weight loss. Genetic testing of his sputum confirmed that his illness is caused by drug-susceptible TB. The woman and her children have latent TB infection that was detected by a rapid assay for gamma interferon response performed on a fingerstick sample of blood; they are feeling well and have normal chest radiographs. You place these four family members on the standard regimen for LTBI:  12 weekly doses of a single pill (INH and rifapentine combined) delivered by DOT. You assure the family that they will all be protected from the disease affecting their husband and father. The woman is relieved to learn that she and her children will be able to take such a simple regimen of medicines. Her husband is now at home and has been started on the standard 4-month regimen for drug-susceptible TB: thrice-weekly DOT with three drugs, including a rifamycin and a quinolone.

Sound like an unrealistic fantasy? Perhaps not, and you and your patients may have an opportunity to help make these fantasies come true. Read on.

Consider the advances in TB therapy that have been made in the last 50 years. Standard TB regimens in the 1950s and 1960s consisted of daily therapy with multiple medications, often including injectables, for 18 to 24 months. Clinical trials conducted in the 1960s and 1970s by the British Medical Research Council in collaboration with groups in Africa, India, and Hong Kong established the effectiveness of 6-month “short course” therapy with rifampin-based regimens.1 Many practitioners in the United States were not willing to adopt the use of regimens that had not been studied in a domestic population and were concerned about the possible toxicity of rifampin. In the early 1970s, public health clinics across the United States enrolled 822 patients in a United States Public Health Service (USPHS) trial comparing three rifampin-based regimens. The results of this trial helped establish 600 mg as the effective dose of rifampin for use in combination chemotherapy and demonstrated acceptably low toxicity of the isoniazid and rifampin combination.2

The results of two clinical trials published in 1990 established the basis for our current standard of care for TB in the United States. USPHS Study 21 enrolled over 1400 patients from 22 clinics in 13 states in the 1980s and demonstrated the effectiveness and tolerability of a 6-month INH/RIF regimen (supplemented with PZA for the first 2 months) compared with a 9-month INH/RIF regimen.3 The other trial of 125 patients studied by the Denver Department of Health demonstrated the effectiveness of the largely intermittent 6-month “Denver short course” delivered by DOT, a regimen used by the majority of U.S. public health clinics today.4

During the 1970s, public health and Veterans Administration (VA) clinics across the United States enrolled patients in much greater numbers in studies of the effectiveness and safety of INH for prophylaxis of TB in PPD-positive individuals.5,6  The many clinical trials conducted in the United States and abroad provide the evidence to support our current successful approach to the therapy of latent and active TB.

But, as the reader well knows, we have the need for simpler, shorter, safer, and even more successful regimens for all TB patients. Additionally, TB/HIV coinfection and the growing prevalence of MDR TB in some global areas bring new challenges to the treatment and control of TB. How can we arrive at the fantasy described above? New regimens will only result from careful design and conduct of clinical trials. The Tuberculosis Trials Consortium (TBTC) is an investigator-driven consortium funded by CDC since 1995. The purpose of the TBTC is to continue earlier work done by the USPHS and the VA by conducting programmatically relevant research that expands treatment and prevention options for TB control worldwide. 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.

You may not know that U.S. TB treatment guidelines have already been informed by the results of TBTC studies. The first two TBTC trials studied intermittent regimens using rifapentine (in HIV-infected and HIV-uninfected patients) and rifabutin in HIV-infected patients. TBTC Study 22 results set the standard and limitations for the use of rifapentine-based regimens for low-risk TB patients and alerted the TB community to rifampin-resistance developing in HIV-infected persons, resulting in rifapentine contraindications in this population.7 TBTC Study 22 also identified TB patients at high-risk for TB treatment failure or relapse based on the combined finding of cavity on initial chest x-ray and persistently positive sputum cultures after the first 8-weeks of therapy.  This led to the new emphasis on the timing of sputum conversion and prolonging therapy in those at highest risk.  This should significantly reduce the number of re-treatment cases we all have to deal with.

TBTC Study 23 determined that rifamycin-based intermittent therapy of persons with HIV-TB and low CD4 counts resulted in unacceptable rates of rifampin-resistant TB.  These research results shaped the majority of changes made in the 2003 TB treatment guidelines.8

Currently the TBTC is enrolling patients into five TB treatment and prevention trials.  The U.S. clinical sites comprise public health departments, academic medical centers, and VA Medical Centers. Over the next 4 years, TBTC sites will enroll over 300 patients per year in studies of active TB and over 1500 patients per year in Study 26, a study of treatment for latent TB infection. Study 26 is a trial of treatment of LTBI comparing 3-month once-weekly isoniazid and rifapentine (the short regimen referred to in the 2024 “fantasy” above) vs. standard 9-month isoniazid therapy.  This large study will have a total enrollment of 8,000 high risk PPD-positive patients; over 3,500 have been enrolled to date. History has taught us the powerful impact of clinical trials. TBTC investigators hope you and your clinic will continue or begin to participate in these important opportunities to improve the future of TB treatment.

Many of the clinics participating in TBTC work have found there are also more immediate benefits to participation. Claire Murphy, RN, a former public health nurse and current study coordinator for the Boston TBTC, writes the following about TBTC:

"It enhances patients’ involvement through active participation in their own plan of care. Patients who feel they are part of the ‘process’ actively contribute to laying the groundwork for those future regimens of safe and effective short-course chemotherapies. Ongoing collaboration with the TBTC allows for more opportunities, strategies, and resources to target those 'hard-to-reach' patients. A partnership with your local TBTC site will facilitate optimum completion of therapy rates. To our local public health departments, these high-risk patients who are sought out for treatment are waiting for more improved and tolerable regimens. The question is, ‘Are you ready for them?’ Come, work with us!”

For further information, contact the Clinical and Health Systems Research Branch, DTBE, National Center for HIV, STD, and TB Prevention, CDC, Mailstop E-10, Atlanta, GA, 30333. Elsa Villarino, MD, MPH, is the Team Leader for the TB Trials Consortium.

Tel: (404) - 639-8123
Fax: (404) - 639-8961
Email: tbtc@cdc.gov
Internet

—Reported by Susan M. Ray, MD
Emory University

References

  1. Iseman MD, Sbarbaro JA. Short course chemotherapy of tuberculosis: Hail Britannia (and friends). Am Rev Resp Dis 1991;143:697-8.
  2. Long MW, Snider DE, Farer LS.  USPHS cooperative trial of three rifampin-isoniazid regimens in the treatment of pulmonary tuberculosis. Am Rev Resp Dis 1979;119:879-94.
  3. Combs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and accepatability. Ann Intern Med 1990;112;397-406.
  4. Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis: a twice-weekly, directly observed, and cost-effective regimen. Ann Intern Med 1990;112:407-415.
  5. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Adv Tuberc Res 1970;17:28--106.
  6. Kopanoff DE, Snider, Jr., DE, and Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis 1979;117:991-1001.
  7. TB Trials Consortium. Once-weekly rifapentine and isoniazid versus twice-weekly rifampin and isoniazid in the continuation phase of therapy for drug-susceptible pulmonary tuberculosis: a prospective, randomized clinical trial. Lancet 2002;360;528-34.
  8. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-662.

TBTC Studies and Publications

  • Safety and Efficacy Trials

    Study 22: Efficacy trial of once-weekly isoniazid and rifapentine in the continuation phase of therapy for pulmonary TB (TB Trials Consortium. Lancet 2002; 360: 528-34.)

    Study 23: Single-arm trial evaluating twice-weekly rifabutin for treatment of HIV-associated TB (completed; manuscript submitted)

    Study 24: Efficacy of intermittent therapy for patients with isoniazid -resistant TB or isoniazid intolerance (enrollment completed)

    Study 25: Phase I-II dose escalation study using same design as Study 22, randomizing to 600, 900, or 1200 mg of once-weekly rifapentine (Bock N, et al.  Amer J Respir Crit Care Med 2002; 165: 1526-1530)

    Study 27:  Phase II study of activity and tolerability of moxifloxacin vs. ethambutol in 1st 8 weeks of TB treatment (enrollment completed March 8, 2005)

    Study 28:  Phase II evaluation of moxifloxacin-based, isoniazid-sparing regimen in 1st 8 weeks of TB treatment (anticipated start in April 2005)

  • Pharmacokinetic Studies

    Study 22 PK: Evaluate isoniazid, rifampin, and rifapentine PK in Study 22 (Weiner et al. Am J Respir Crit Care Med 2003; 167: 1341-7; Weiner M et al. Am J. Respir Crit Care Med 2004; 169; 1191-7)

    Study 23A, B & C: Evaluate rifabutin and isoniazid, efavirenz and nelfinavir interaction in persons with HIV-TB (Ongoing)

  • Diagnostic Studies

    NAA Substudy: Study of the performance of several nucleic acid amplification methodologies in diagnosis and management of active TB (Ongoing)

  • Prevention Trials

    Study 26: Trial of treatment of latent TB infection comparing 3-month once-weekly isoniazid + rifapentine vs. 9-month isoniazid therapy (Ongoing)

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination - http://www.cdc.gov/tb

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