Rifampicin drug resistance tests for tuberculosis: challenging the gold standard

Setting:The rapid diagnosis of rifampicin resistance is hampered by reported insufficient specificity of molecular techniques for detection of rpoB mutations. Objective:To document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance.Design:Sequencing directly from sputum of first failure or relapse patients without phenotypic selection; comparison of standard re-treatment regimen outcome by mutation. Results:Among all rpoB mutations, the best documented "disputed" rifampicin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro and 572Phe), made up 13.1% and 10.6% in Bangladesh and Kinshasa respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampicin resistant in routine LJ proportion DST (78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. Conclusions:Rifampicin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampicin DST method. Even at low prevalence, a rifampicin resistant result issued by a competent laboratory may not warrant confirmation, although this needs to be confirmed also for molecular results among new cases. However, a susceptible result should be questioned when suspicion is very high, and further DST using a different system (i.e. geno- after phenotypic) would be fully justified.