Association between Regimen Composition and Treatment Response in Patients with Multidrug-Resistant Tuberculosis: A Prospective Cohort Study

Abstract

BackgroundFor treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.Methods and FindingsWe analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph.In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen).The main limitation of this analysis is that it is based on observational data, not a randomized trial, and...

Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China

“…2). This relationship has been shown in previous studies (2,22). In addition, there were no differences in important variables related to treatment outcome, except for the higher frequency of pulmonary cavities and severe pulmonary disease on CXR in the group of patients with MICs above the CART-derived breakpoints.…”

“…Susceptibility testing is an important guide for clinicians to evaluate the patient's likely response to a particular drug (22). The critical concentration of SLDs recommended by the WHO are based on wild-type, susceptible M. tuberculosis isolates.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…42,69,128 Indeed, some settings-from Estonia 129,130 to New York 131 -have seen steeper declines in the incidence of drug-resistant tuberculosis than in tuberculosis as a whole after adopting interventions to control the transmission of drug-resistant tuberculosis. Typically, these measures included universal DST, 132 individualised treatment, 133 access to tuberculosis care, 134 and sustained efforts to improve treatment completion, which is only achieved in two-thirds of cases, even in well functioning programmes. 135 The recent recommendation of a shorter-course MDR tuberculosis regimen in patients with rifampicinresistant or MDR tuberculosis not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable drugs has been excluded or is considered highly unlikely, could substantially improve treatment compliance and thus reduce transmission from patients who might otherwise fail to adhere to the standard 24-month toxic MDR tuberculosis regimen.…”

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

“…In the case of rifampin, a prior study found that phenotypic DST does not capture some clinically relevant resistance conferred by disputed rpoB mutations that had previously been considered of indeterminate significance; these were associated with a rate of failure or relapse of first-line retreatment of 63% (6). For pyrazinamide, only a few studies have directly evaluated the correlation between in vitro resistance with clinical outcomes (12,(29)(30)(31)(32). One of these reported that patients whose isolates had an MIC breakpoint of over 50 mg/liter had poor sputum conversion rates (12).…”