Drug MICs and relapse risk in TB – is there a correlation?

N Engl J Med. 2018 Aug 30;379(9):823-833

Contributed by Dr Abi Manesh

While we are aware that a small percentage of patients (5%) with drug-susceptible tuberculosis have a relapse after 6 months of therapy, the underlying reasons are not clear. The authors evaluated whether any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint could predict the relapse risk after treatment.

Using available trial data samples they evaluated MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin) using methods which are not available in regular clinical practice.

In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively.

The most important message of this trial is that it highlights the short comings of the artificial black and white separation of "susceptible" or "resistant," isolates made for clinical use. Few things unexplained are in the INH cohort the risk did not show a steady increase with increasing MICs – actually there is a dip in the relapse risk in Fig 1A. While it improves our understanding of tuberculosis, it may not change existing clinical practice.