Whole Genome Sequencing Assessing Impact of Diabetes Mellitus on Tuberculosis Mutations and Type of Recurrence in India.

INTRODUCTION Evidence describing the impact of diabetes mellitus (DM) on the recurrence and mutation rate of Mycobacterium tuberculosis (Mtb) is limited. METHODS This study was nested in three cohort studies of tuberculosis (TB) patients with and without DM in India. Paired Mtb isolates recovered at baseline and treatment failure/recurrence underwent whole genome sequencing. We compared acquisition of single nucleotide polymorphisms (SNP), TB drug resistance mutations and type of recurrence (endogenous reactivation [<8 SNPs] or exogenous reinfection [≥8 SNPs]) by DM status. RESULTS Of 1633 enrolled in the three parent cohorts, 236 (14.5%) had microbiologically confirmed TB treatment failure/recurrence; 76 Mtb isolate pairs were available for sequencing (22 in TB-DM and 54 in TB-only). The SNP acquisition rate was overall was 0.43 (0.25 - 0.64) per 1 person year (PY); 0.77 (0.40 - 1.35) per 1PY and 0.44 (0.19 - 0.86) per 1 PY at treatment failure and recurrence, respectively. Significant difference in SNP rates by DM status was seen at recurrence (0.21 (0.04 - 0.61) per 1PY for TB-only vs. 1.28 (0.41 - 2.98) per 1PY for TB-DM; p=0.02). But no significant difference in SNP rates by DM status was observed at treatment failure. Acquired TB drug resistance was seen in 4/18 (22%) in TB-DM versus 4/45 (9%) in TB-only (p=0.21). Thirteen (17%) participants had exogenous reinfection; reinfection rate at recurrence was 25% (3/12) for TB-DM vs. 17% (4/24) in TB-only (p=0.66). CONCLUSION Considerable intra-host Mtb mutation rates were present at recurrence among patients with DM in India. One-fourth of patients with DM had exogenous reinfection at recurrence.