Risk for relapse in drug-susceptible TB cases rises with MIC values

“Our results suggest that measurable characteristics of the infecting Mycobacterium tuberculosis strain are at least as important as clinical, radiologic and microbiologic features that have previously associated with relapse in patients with tuberculosis,” Roberto Colangeli, PhD, assistant professor in the department of medicine at Rutgers New Jersey Medical School, and colleagues wrote.

They said their findings “may be useful in selecting patients who can be safely treated with shorter-duration regimens.”

According to the study, approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, and roughly 20% of patients have a relapse after 4 months of short-course therapy. Lengthy treatments are a burden on public health systems and increase the risk for toxic effects, nonadherence and resistance, Colangeli and colleagues said.

“The standard 6-month, multidrug therapy that is recommended for the initial treatment of drug-susceptible tuberculosis represents a balance between the benefits and liabilities of long-term treatment and the risk of relapse associated with shortened treatments,” they wrote. “No measures are available for reliably assigning patients with tuberculosis to different risk groups and treatment durations.”

For the study, Colangeli and colleagues used data from the Tuberculosis Trials Consortium Study 22, which was conducted from April 1995 through February 2001 and included 1,004 adult patients with drug-susceptible tuberculosis. These patients had completed at least 8 weeks of standard four-drug therapy (rifampin, isoniazid, pyrazinamide, ethambutol) before being randomly assigned to receive either once-weekly rifapentine with isoniazid or twice-weekly rifampin plus isoniazid for an additional 16 weeks. Colangeli and colleagues then assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint.

Of the 1,004 patients enrolled, 803 completed follow up or had an outcome event, 11 had clinical or microbiologic treatment failure, and 63 had a bacteriologically confirmed relapse, Colangeli and colleagues reported. They noted several characteristics common among patients who experienced relapse, including being underweight, the presence of cavitation and bilateral disease on chest radiography, being white, and sputum-culture positivity after 8 weeks of treatment.

As for the association between MIC values and relapse, Colangeli and colleagues found that:

• the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg/ml among patients who had a relapse and 0.0286±0.0092 μg/ml among those who were cured, representing a higher value in the relapse group by a factor of 1.17 (95% CI, 1.03-1.33; adjusted P = 0.02);
• and the corresponding MIC values of rifampin were 0.0695±0.0276 μg/ml among the patients who had a relapse and 0.0453±0.0223 μg/ml among those who were cured — a higher value in the relapse group by a factor of 1.53 (95% CI, 1.27-1.86; adjusted P < 0.001).

According to Colangeli and colleagues, higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences.

“We found that decrements of MIC values of isoniazid and rifampin that were below the standard resistance breakpoint in drug-susceptible M. tuberculosis strains had an influence on treatment outcomes, with the risk of relapse increasing together with the MIC value,” they wrote. “In addition, we confirmed these findings in isolates obtained from patients with tuberculosis in a validation cohort. Additional studies that are performed in larger, well-defined prospective cohorts and that include MIC testing of pretreatment culture isolates will be useful to better validate these findings.”

Colangeli R, et al. N Eng J Med. 2018;doi:10.1056/NEJMoa1715849.

Source: Healio