The Impact of Illicit Drug Use on Tuberculosis Transmission in South Africa

Abstract

Tuberculosis (TB) remains the leading cause of death by infectious disease globally. South Africa carries a disproportionately high burden of TB incidence, compounded by high rates of co-infection with HIV, poverty, crowding, unemployment, and undernutrition. The role of illicit drug use, specifically concurrent methamphetamine and mandrax smoking, in shaping TB transmission dynamics has not previously been studied using genomic approaches. Using whole- genome sequencing data from 462 culture-confirmed TB patients across two observational studies in Worcester, Western Cape, South Africa (TRUST and TOTAL), transmission clusters were constructed at a 25 SNP distance threshold and analyzed using the Bayesian transmission inference framework BREATH to reconstruct pairwise transmission probabilities. These posterior probabilities were used as outcomes in a multivariate regression analysis, including infector-level negative binomial and logistic models and a dyadic generalized estimating equation (GEE) model, incorporating behavioral concordance between infector-infectee pairs. Concurrent methamphetamine and mandrax use was independently associated with increased secondary infection counts at the infector levels (IRR = 1.55, 95% CI: 1.02-2.36), while the dyadic analysis revealed that concordance in polysubstance use was more likely than other non- concordance or no polysubstance use between infector and infectee pairs (β=0.37, 95% CI: -0.02 to 0.76). These findings identify illicit polysubstance users as a high-risk, hard-to-reach population contributing disproportionately to onward TB transmission and highlight the potential value of integrating TB screening and harm reduction strategies within drug-use networks to interrupt transmission in high-burden settings.