In the Journals

More than five drugs for MDR-TB improve treatment response

Recent findings published in PLoS Medicine suggested that treating patients with multidrug-resistant tuberculosis with a greater number of drugs than is currently recommended by WHO might improve a patient’s response to treatment. In addition, the findings showed that access to baseline drug susceptibility testing could help guide treatment.

“In our analysis, greater numbers of potentially effective drugs in [a multidrug-resistant tuberculosis (MDR-TB)] treatment regimen were associated with accelerated sputum culture conversion,” Courtney M. Yuen, PhD, associate epidemiologist at Brigham and Women’s Hospital, and colleagues wrote. “Patients receiving individualized regimens containing a minimum of five probably effective drugs for prolonged periods after sputum culture conversion have been shown to have decreased risks of treatment failure, death, and relapse compared to patients receiving fewer drugs.”

WHO guidelines for MDR-TB recommend a regimen of at least four drugs that are likely to be effective as well as pyrazinamide. The guidelines indicate that regimens based directly on drug susceptibility testing (DST) offer only marginal benefit to patients. However, the researchers noted that regimens containing a greater number of drugs have improved outcomes in some patients, and that DST results have been previously associated with higher odds of treatment success.

The researchers analyzed data from the Preserving Effective Tuberculosis Treatment Study, an observational study of 1,659 patients treated for MDR-TB from 2005 to 2010 in nine countries. For all patients, monthly sputum samples were collected, and DST was performed. Yuen and colleagues looked at 1,137 patients with known baseline DST results, while excluding patients with extensively drug-resistant TB. The researchers followed the patients for a median of 20 months. The primary outcome was sputum culture conversion per drug as an indicator of the bactericidal effect of treatment. They defined sputum culture conversion as two consecutive negative cultures of sputum samples collected at least 30 days apart. The researchers used Cox proportional hazards regression, which controlled for setting-associated confounding variables and adjusted for baseline treatment history, resistance pattern, sputum smear result, the extent of disease on chest radiograph, and the number of drugs to which a patient’s isolates were resistant.

Yuen and colleagues found that an average of at least six drugs per day increased the odds of sputum culture conversion compared with five drugs per day (adjusted HR = 1.36; 95% CI, 1.09-1.69). Including pyrazinamide in a TB regimen (aHR = 2; 95% CI, 1.65-2.41), as well as drugs to which isolates were susceptible according to baseline DST (aHR = 1.65; CI, 1.48-1.84, per drug), increased the odds of sputum culture conversion compared with drugs to which DST indicated resistance at baseline (aHR = 1.33, 95% CI, 1.18-1.51, per drug). Including drugs that had not been tested by DST increased the odds of sputum culture conversion only if the regimen contained a minimum of three effective drugs (aHR = 1.39; 95% CI, 1.09-1.76).

The researchers noted that the study was not randomized — the main limitation of their analysis, they said.

“Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens,” Yuen and colleagues wrote. “New rapid DST techniques will be required if knowledge of baseline drug resistance is to guide regimen composition at the beginning of treatment.” – by Will Offit

Disclosure: The researchers report no relevant financial disclosures.

Recent findings published in PLoS Medicine suggested that treating patients with multidrug-resistant tuberculosis with a greater number of drugs than is currently recommended by WHO might improve a patient’s response to treatment. In addition, the findings showed that access to baseline drug susceptibility testing could help guide treatment.

“In our analysis, greater numbers of potentially effective drugs in [a multidrug-resistant tuberculosis (MDR-TB)] treatment regimen were associated with accelerated sputum culture conversion,” Courtney M. Yuen, PhD, associate epidemiologist at Brigham and Women’s Hospital, and colleagues wrote. “Patients receiving individualized regimens containing a minimum of five probably effective drugs for prolonged periods after sputum culture conversion have been shown to have decreased risks of treatment failure, death, and relapse compared to patients receiving fewer drugs.”

WHO guidelines for MDR-TB recommend a regimen of at least four drugs that are likely to be effective as well as pyrazinamide. The guidelines indicate that regimens based directly on drug susceptibility testing (DST) offer only marginal benefit to patients. However, the researchers noted that regimens containing a greater number of drugs have improved outcomes in some patients, and that DST results have been previously associated with higher odds of treatment success.

The researchers analyzed data from the Preserving Effective Tuberculosis Treatment Study, an observational study of 1,659 patients treated for MDR-TB from 2005 to 2010 in nine countries. For all patients, monthly sputum samples were collected, and DST was performed. Yuen and colleagues looked at 1,137 patients with known baseline DST results, while excluding patients with extensively drug-resistant TB. The researchers followed the patients for a median of 20 months. The primary outcome was sputum culture conversion per drug as an indicator of the bactericidal effect of treatment. They defined sputum culture conversion as two consecutive negative cultures of sputum samples collected at least 30 days apart. The researchers used Cox proportional hazards regression, which controlled for setting-associated confounding variables and adjusted for baseline treatment history, resistance pattern, sputum smear result, the extent of disease on chest radiograph, and the number of drugs to which a patient’s isolates were resistant.

Yuen and colleagues found that an average of at least six drugs per day increased the odds of sputum culture conversion compared with five drugs per day (adjusted HR = 1.36; 95% CI, 1.09-1.69). Including pyrazinamide in a TB regimen (aHR = 2; 95% CI, 1.65-2.41), as well as drugs to which isolates were susceptible according to baseline DST (aHR = 1.65; CI, 1.48-1.84, per drug), increased the odds of sputum culture conversion compared with drugs to which DST indicated resistance at baseline (aHR = 1.33, 95% CI, 1.18-1.51, per drug). Including drugs that had not been tested by DST increased the odds of sputum culture conversion only if the regimen contained a minimum of three effective drugs (aHR = 1.39; 95% CI, 1.09-1.76).

The researchers noted that the study was not randomized — the main limitation of their analysis, they said.

“Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens,” Yuen and colleagues wrote. “New rapid DST techniques will be required if knowledge of baseline drug resistance is to guide regimen composition at the beginning of treatment.” – by Will Offit

Disclosure: The researchers report no relevant financial disclosures.