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U.S. Department of Health and Human Services

  

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TB Notes 3, 2002

Updates from the Research and Evaluation Branch

Meeting on Rifamycins

On April 8-9, the Global Alliance for TB Drug Development, in collaboration with the CDC and the National Institutes of Health’s National Institute on Allergies and Infectious Diseases (NIAID), sponsored a workshop on long-acting rifamycins. The meeting, which was held at NIAID offices in Bethesda, Maryland, gathered some 30 scientists from academia, industry, and public research institutes.

Data on the marketed, long-acting rifamycins, rifapentine and rifabutin, were critically reviewed, especially with regard to efficacy of widely-spaced intermittent regimens in HIV-positive TB patients and to their interactions with antiretroviral drugs. Protein-binding effects on the pharmacokinetics and pharmacodynamics of rifamycins were further discussed. Data on two newer rifamycins in early clinical development, rifalazil and rifametane, as well as several other compounds (FCE 22250, FCE 22807, and rifalazil analogues), were also reviewed. Presentations were given on research regarding mechanisms of action that could lead to enhanced sterilizing activity of the rifamycins, such as crystallography of targets and apoptosis.

The meeting participants reached the following conclusions: 1) of the compounds discussed, rifapentine remains of greatest interest; 2) further work on rifalazil and rifametane would be required to raise interest in those drugs; 3) studies of higher doses of daily rifampin aimed at increasing the sterilizing activity and shortening treatment are warranted; and 4) a program to develop additional novel rifamycins with improved activity, while feasible, is not a high priority, although further investigations of older compounds and screening of rifamycin libraries might be of interest.

CDC’s TB Trials Consortium remains quite interested in additional studies of rifapentine. Recent experimental studies have suggested that the efficacy of once-weekly rifapentine-based regimens may be markedly improved with the addition of moxifloxacin as a companion drug. In addition, efficacy may be increased with the use of the 900-mg dose of rifapentine that is currently being used in TBTC Study 26, a large randomized clinical trial of once-weekly rifapentine and isoniazid for the treatment of latent TB infection.

—Reported by Rick O’Brien, MD
Division of TB Elimination

Report on the 11th Semiannual Meeting of the TB Trials Consortium

The TB Trials Consortium (TBTC) held its 11th Semiannual Meeting in Atlanta on May 17-18, immediately preceding the 98th International Conference of the American Thoracic Society (ATS). All TBTC field sites were represented at the meeting. The following key issues were discussed at the TBTC meeting:

  • Progress on Study 26 (a study of the effectiveness and tolerability of weekly rifapentine and isoniazid for 3 months versus daily isoniazid for 9 months for the treatment of latent TB infection): Enrollment was 669 just prior to the meeting, and continues to grow. The preplanned toxicity evaluation (required by the protocol after 644 patients had been enrolled) took place in early summer, and sites are gearing up for a major enrollment effort.
  • The developing design of Study 27 (a phase 2 study evaluating the activity and tolerability of moxifloxacin during the first 2 months of treatment for pulmonary TB): This study is expected to prepare the way for a phase 3 trial of moxifloxacin-based, shortened therapy for pulmonary TB. The study is expected to be a full-scale collaboration between TBTC and the NIAID-funded TB Research Unit field site in Kampala, Uganda. The TBRU expects to enroll half the patients for this trial, and is represented on the protocol team by Dr. John Johnson of Case Western Reserve University, and by Dr. Charles Daley of the University of California at San Francisco, whose institution participates in both research groups. Also participating on the protocol team is Dr. Mark Kunkel from Bayer, the manufacturer of moxifloxacin. This substantive engagement on the part of the manufacturer of moxifloxacin has been extremely important in helping the protocol team move rapidly to an appropriate study design.
  • The design and implementation of Study 26A (a substudy evaluating the impact of chronic viral hepatitis on patient discontinuation of treatment for latent TB infection due to hepatotoxicity in Study 26): as part of this substudy, field sites are involved with the many issues presented by coinfection with hepatitis B and hepatitis C viruses. Testing and counseling related to these viral infections — for example, potential for transmission through sexual contact (substantial for B, low but not zero for C), or casual contact (low for both) — was discussed extensively during a plenary session and in training sessions with the site coordinators.
  • Further work with long-acting or high-dose rifamycins: Dr. Charles Peloquin from National Jewish Medical Center in Denver reviewed data on the pharmacokinetics of rifampin, and suggested that the use of higher-dose rifampin regimens merits further evaluation. Dr. Jacques Grosset shared data from studies of rifapentine in the murine tuberculosis model, providing further support for TBTC work with this promising newer rifamycin.

In other segments of the meeting, Dr. Bernard Fourie from the South African Medical Research Council provided an update on the efforts to develop a TB clinical trials collaboration in the Republic of South Africa and Dr. Naomi Bock, now chair of one of CDC’s IRBs, provided an update on the TBTC efforts to implement a "central IRB" process. Finally, the group reviewed its planned presentations for the ATS Conference, which included five posters, an oral presentation, a noontime session devoted to TBTC work, invited presentations by several TBTC members, and three symposia or mini-symposia chaired and organized by TBTC investigators. More information on the TBTC is available at its Web site, http://www.cdc.gov/nchstp/tb/tbtc.

—Reported by Andrew Vernon, MD
Division of TB Elimination

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
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