This article is more than 5 years old. Information may no longer be current.
High-dose rifampicin shows promise in TB
Click Here to Manage Email Alerts
A rifampicin dose of 35 mg/kg was safe for treating patients with tuberculosis, and produced a faster culture conversion in liquid media, study data show.
“Tuberculosis is now the leading infectious disease killer worldwide. Treatment regimens last at least 6 months, so shorter, safer and more effective regimens for drug-sensitive tuberculosis are needed as part of the global strategy to eliminate the disease,” Martin J. Boeree, PhD, of the department of lung diseases at Radboud University Medical Center, Nijmegen, Netherlands, and colleagues wrote. “The standard dose of rifampicin (10 mg/kg) was chosen in the 1960s, primarily because of cost. However, results of several studies in mice showed that higher doses can accelerate cure, and higher doses seemed to increase sputum culture conversion in clinical trials.”
Researchers conducted a randomized, controlled, open-label trial of 365 patients with untreated TB in South Africa and Tanzania. Patients were randomly assigned to several treatment arms: 35 mg/kg rifampicin, isoniazid, pyrazinamide and ethambutol (n = 63); 20 mg/kg rifampicin plus isoniazid, pyrazinamide and SQ109 (n = 57); 10 mg/kg rifampicin plus isoniazid, pyrazinamide and SQ109 (n = 59); 10 mg/kg rifampicin plus isoniazid, pyrazinamide and moxifloxacin (n = 63); or a control arm (n = 123). The control therapy included 10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide and 15 to 20 mg/kg or ethambutol for 8 weeks, followed by rifampicin and isoniazid for 18 weeks. All patients were assigned to each drug orally 7 days a week.
Researchers ended enrollment in the two arms assigned to SQ109 early because they did not meet the study’s interim efficacy threshold. The group assigned to 35 mg/kg rifampicin had a median culture conversion time of 48 days in liquid media, compared with 62 days in the control group (HR = 1.78; 95% CI, 1.22-2.58), Boeree and colleagues reported. No other experimental arms showed a faster culture conversion time than the control group. The researchers reported that all arms of the study had similar culture conversion times in solid media.
Forty-five patients (12%) reported adverse events of grade 3 or higher. One patient in the 35 mg/kg rifampicin arm died 13 weeks after treatment ended; however, the researchers noted this patient had complained of chest pains in the hours before death and the death was not likely related to rifampicin. Eleven patients experienced treatment failure, with only one treatment failure occurring in the 35 mg/kg rifampicin arm.
“The advantage of high dose rifampicin that the drug is widely available at low cost and implementation could take place broadly and quickly. A larger pill burden is a potential disadvantage, as available rifampicin formulations are not adapted to the higher doses,” Boeree and colleagues wrote. “Importantly, the multi-arm, multi-stage concept has been shown to be feasible in a multicenter tuberculosis high burden setting, generating evidence to make a decision for whether or not to proceed to phase 3, and could greatly speed regimen development at reduced cost. In this phase 3 trial, a regimen with high dose rifampicin can be tested for safety and tolerability, potential to shorten duration of treatment and ability to prevent the emergence of resistance to rifampicin.”
SQ109 for tuberculosis should not be ruled out, wrote Rovina Ruslami, MD, PhD, faculty of medicine at Universitas Padjadjaran, Bandung, Indonesia, and Dick Menzies, MD, MSc, of the respiratory epidemiology and clinical research unit of the Montreal Chest Institute, in an accompanying editorial. They warned that rifampicin requires “further evaluation work” before a phase 3 trial could occur.
“Boeree and colleagues are very optimistic that high dose rifampicin might be useful in shortening current treatment for drug sensitive TB; we share their optimism, but in a more limited dose,” Ruslami and Menzies wrote. – by Andy Polhamus
Disclosure: The researchers report no relevant financial disclosures.
Click Here to Manage Email Alerts