PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading infectious disease killer globally and leading cause of death in persons with HIV. The most effective way to reduce TB incidence and mortality is to interrupt transmission. However, this requires finding and treating individuals with TB disease early. The current primary approach to case finding— household contact tracing—identifies <20% of transmissions in high burden settings, leaving a clear and urgent need to identify new groups and settings where TB transmission occurs. Illicit drug use is associated with higher TB infection prevalence and disease incidence, likely due to significant within-group transmission and/or clustered vulnerability. Interrogation of illicit drug use networks for TB transmission, therefore, holds great potential as a target for early case identification and linkage to treatment, with potential benefit for halting transmission to the broader population. Investigators at Boston Medical Center, Stellenbosch University, the South African Medical Research Council, Boston University School of Public Health and the Desmond Tutu HIV Foundation propose to conduct the first study to assess TB risk and disease burden among illicit drug use networks in a high TB/HIV setting and to identify mechanisms for accelerated transmission in this population. We will use respondent driven sampling to recruit 750 individuals, with and without HIV disease, who smoke illicit drugs (methamphetamine and methaqualone) and assess their TB exposure, risk of disease progression, and TB disease burden. Among individuals found to have TB disease, we will leverage whole genome sequencing and social contact interviews to estimate the proportion of cases in this network resultant from recent transmission. We will capture cough frequency and use novel bioaerosol sampling techniques to compare physiologic characteristics of infectiousness between persons who smoke illicit drugs compared to those who do not. Knowledge from this study will provide the basis for a new, focused strategy to interrupt TB transmission in persons who smoke illicit drugs and provide insight into the degree that such transmission fuels overall community spread. These results have potential for generating interventions applicable to many settings where illicit drug use intersects with TB and HIV.

PROJECT NARRATIVE Tuberculosis (TB) is the leading infectious disease killer globally; the most effective way to reduce the number of new TB cases and deaths is by finding and treating individuals with TB disease early so they do not infect others. People who smoke illicit drugs have higher rates of TB infection and disease compared to non-users, likely reflecting significant within-group transmission and/or clustering of particularly vulnerable individuals, making them a prime target for interventions. In this prospective study, we will assess TB exposure, risk of disease progression, and disease burden among persons who smoke illicit drugs and aim to characterize reasons that persons who smoke illicit drugs may be particularly efficient at spreading TB.