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Novel Regimens
There are several new regimens for drug-susceptible and resistant TB in clinical trials. These efforts have been done for shortening the duration of chemotherapy in drug-susceptible and resistant TB, and for increasing efficacy for drug-resistant TB.
Regimens for Shortening the Duration of Tuberculosis Treatment
Treatment shortening could yield a breakthrough in TB control, as the long duration of treatment leads many patients to default from treatment early. A randomized equivalence trial evaluating whether treatment duration could be shortened to a 4-month regimen using standard doses of rifampicin in patients with a low risk of relapse (with noncavitary disease whose sputum cultures converted to negative after 2 months) showed significantly higher rates of relapse in the 4-month arm than the standard 6-month arm. This higher relapse rate in the shorter duration treatment arm may be due to the failure to eradicate dormant bacilli. Therefore, successful regimens that shorten the duration of treatment need to focus on introducing new drugs with novel mechanisms of action.
In that sense, fluoroquinolones might have an important role. A recent randomized trial, however, showed higher relapse rate of 15% and 11% in the 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampin, and pyrazinamide (2GHRZ3/2GHR3 or 2MHRZ3/2MHR3), compared with 6% in the standard 6-month thrice-weekly treatment (2EHRZ3/4HR3) during 24 months after the end of treatment. Currently, three noninferiority trials, which are using a daily dosing regimen at least intensive phase instead of an intermittent dosing regimen, are assessing the use of fluoroquinolones to shorten the treatment duration to 4 months. OFLOTUB (A Multicentre, Randomised, Control Trial of Ofloxacin-Containing, Short-Course Regimen for the Treatment of Pulmonary Tuberculosis; NCT00216385) is comparing the standard 6-month regimen with a regimen consisting of a 2-month intensive phase in which gatifloxacin is substituted for ethambutol, followed by a 2-month maintenance phase of gatifloxacin, isoniazid, and rifampin (2GHRZ/2GHR). Follow-up data have been obtained, but results have not yet been published. REMox TB (NCT00864383) is comparing standard 6-month therapy with two study regimens [2 months of moxifloxacin, isoniazid, rifampin, and pyrazinamide followed by 2 months of moxifloxacin, isoniazid, and rifampin (2MHRZ/2MHR) or 2 months of ethambutol, moxifloxacin, rifampin, and pyrazinamide followed by 2 months of moxifloxacin and rifampin (2EMRZ/2MR)], and the results are expected in 2014. RIFAQUIN (International Standard Randomised Controlled Trial Number: ISRCTN44153044) is comparing the standard 6-month regimen with two study regimens [2 months of daily ethambutol, moxifloxacin, rifampin, and pyrazinamide followed by 2 months of twice weekly moxifloxacin and rifapentine (2EMRZ/2PM2) or 4 months of once-weekly moxifloxacin and rifapentine (2EMRZ/4PM1) in a maintenance phase], and recruitment for this study has been completed.
New Multidrug-resistant Tuberculosis Treatment Regimens
WHO guidelines on the treatment of MDR-TB recommend an intensive treatment phase of 8 months and a total duration of 20 months in most patients. However, the results of this programmatic management of MDR-TB showed unsatisfactory treatment success rates. An observational study that evaluated standardized treatment regimens for MDR-TB showed them to be highly effective, with infrequent adverse outcomes. Specifically, a regimen consisting of gatifloxacin in combination with ethambutol, pyrazinamide, and clofazimine (5-month maintenance phase), supplemented with kanamycin, prothionamide, and isoniazid during an intensive phase of 4 months or until sputum smear conversion (4KCGEHZP/5GEZC), achieved an 88% cure rate. Although there were significant limitations of this observational study, including a lack of comparable patients treated with WHO-recommended regimens, it is encouraging that this regimen successfully reduced the duration of MDR-TB treatment and increased the cure rate. Based on this report, the STREAM trial (The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with Multidrug-Resistant Tuberculosis; ISRCTN78372190) is now in progress, which is comparing WHO-recommended individualized regimens with 4KCMEHZP/5MEZC (moxifloxacin instead of gatifloxacin).
Fixed-dose Combinations
Fixed-dose combination (FDC) tablets, combining two or more anti-TB drugs, have been manufactured since the 1980s to increase patient compliance with anti-TB treatment. Because FDCs were believed to prevent physician error in medication prescribing and patient error in selectively taking only one drug, they have been widely used. Many observational studies and clinical trials have been conducted to evaluate the effectiveness of FDCs. However, the results have not been consistent. Recently, a systemic review and meta-analysis was performed to determine whether FDCs are effective in treating TB. This systematic review of current evidence does not support the use of FDCs for the purpose of improving treatment outcomes. Instead, FDCs were associated with a trend toward increased risk of treatment failure or disease relapse.
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