Abstract
RationaleA better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.ObjectivesThis study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort.MethodsThis was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.Measurements and Main ResultsIn total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93).ConclusionsThe aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.
Highlights
The aggressive regimen is a robust predictor of multidrug-resistant tuberculosis (MDR-TB) treatment outcome
[2] The combined frequency of cure and completion often remains below 65%. [3,4,5] Even when therapy is designed with access to the full complement of anti-TB agents presently available, outcomes rarely approach the target for TB treatment success. [6,7] The long duration and toxicity of current MDRTB regimens are major obstacles to achievement of universal access to quality treatment. [8,9] In addition, the poor outcomes seen with current regimens mean that, despite treatment, many MDR-TB patients will still develop chronic, highly resistant forms of TB that have a high mortality rate and can be transmitted to others. [10,11]
We evaluated the possibility that the effect of an aggressive regimen was different in patients with confirmed extensively drug resistant TB (XDR-TB, TB caused by strains of M. tuberculosis resistant to at least isoniazid, rifampin, a fluoroquinolone, and a second-line injectable agent), compared to those without XDR-TB, by including an interaction term in the multivariable analysis
Summary
Multidrug-resistant strains of Mycobacterium tuberculosis accounted for approximately 5% of the 6.2 million tuberculosis (TB) cases notified in 2011. [1] Treatment for multidrug-resistant tuberculosis (MDR-TB) typically lasts between 18 and 24 months, and adverse events are common. [2] The combined frequency of cure and completion often remains below 65%. [3,4,5] Even when therapy is designed with access to the full complement of anti-TB agents presently available, outcomes rarely approach the target for TB treatment success (cure at least 85% of patients initiating therapy). [6,7] The long duration and toxicity of current MDRTB regimens are major obstacles to achievement of universal access to quality treatment. [8,9] In addition, the poor outcomes seen with current regimens mean that, despite treatment, many MDR-TB patients will still develop chronic, highly resistant forms of TB that have a high mortality rate and can be transmitted to others. [10,11].For drug-resistant TB, improved treatment depends on introduction of new drugs and optimal use of existing drugs. One influential approach to the composition of regimens recommends a minimum of five drugs to which the isolate was documented or likely to be susceptible. This approach, to composing what we call an ‘‘aggressive’’ regimen, was presented in a 2004 article [16] and used as the foundation for WHO guidelines. If a total of five likely effective drugs cannot be reached using these agents, the aggressive regimen includes other agents of possible utility such as clofazimine, amoxicillin-clavulanate, and/ or a macrolide antibiotic This regimen was recommended to be delivered for 18–24 months past culture conversion, with the injectable agent being administered for 6 months after culture conversion
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