Consequences of mutations missed by the GenoType MTBDR assay in a programmatic setting in South Africa.

BACKGROUND

Rifampicin resistance missed by commercial rapid molecular assays but detected by phenotypic assays may lead to discordant susceptibility results and affect patient management.

OBJECTIVE

This study was conducted to evaluate the causes of rifampicin resistance missed by the GenoType MTBDR and its impact on the programmatic management of tuberculosis in KwaZulu-Natal, South Africa.

METHODS

We analysed routine tuberculosis programme data from January 2014 to December 2014 on isolates showing rifampicin susceptibility on the GenoType MTBDR assay but resistance on the phenotypic agar proportion method. Whole-genome sequencing was performed on a subset of these isolates.

RESULTS

Out of 505 patients with isoniazid mono-resistant tuberculosis on the MTBDR, 145 (28.7%) isolates showed both isoniazid and rifampicin resistance on the phenotypic assay. The mean time from MTBDR results to initiation of drug-resistant tuberculosis therapy was 93.7 days. 65.7% of the patients had received previous tuberculosis treatment. The most common mutations detected in the 36 sequenced isolates were I491F (16; 44.4%) and L452P (12; 33.3%). Among the 36 isolates, resistance to other anti-tuberculosis drugs was 69.4% for pyrazinamide, 83.3% for ethambutol, 69.4% for streptomycin, and 50% for ethionamide.

CONCLUSION

Missed rifampicin resistance was mostly due to the I491F mutation located outside the MTBDR detection area and the L452P mutation, which was not included in the initial version 2 of the MTBDR. This led to substantial delays in the initiation of appropriate therapy. The previous tuberculosis treatment history and the high level of resistance to other anti-tuberculosis drugs suggest an accumulation of resistance.