HIV co-infection is associated with lower tuberculosis bacterial burden independent of time to diagnosis in Botswana, a setting with widespread ART use

HIV co-infection has been shown to be associated with lower tuberculosis (TB) bacterial load in studies conducted prior to widespread availability of antiretroviral therapy (ART). We investigated associations between HIV co-infection and TB bacterial load, accounting for differences in time to TB diagnosis, in a high prevalence setting with widespread ART use. In Gaborone, Botswana, 268 sputum samples from people with newly diagnosed TB were tested with Xpert MTB/RIF Ultra (Xpert). TB bacterial load and time to TB diagnosis were estimated using mean Xpert cycle threshold (CT) and symptom duration, respectively. Multiple linear regression models and causal mediation analysis were used to determine the associations between HIV and Xpert CT and assess the mediating effect of symptom duration. Mean CT values were higher in people living with HIV compared to people without HIV (22.7 vs 20.3, p < 0.001). Among those living with HIV, there was a negative relationship between CD4 count and mean CT value (Spearman’s rho -0.20, p = 0.06). After controlling for gender, age, and symptom duration, HIV status remained associated with CT value, with an average increase of 1.6 cycles (p = 0.009) among people with HIV and CD4 count > 200 cells/mm3 and 2.1 cycles (p = 0.002) in those with a CD4 count ≤ 200 cells/mm3 compared to individuals without HIV. Symptom duration was also found to be associated with CT value (p < 0.05). We found an indirect effect of HIV status on Xpert CT through the mediator, symptom duration (β = 0.33, p = 0.048), accounting for 13.5% of the relationship. Our findings suggest that time to TB diagnosis partially mediates the relationship between HIV status and CT value, but differences in pathophysiology between people with and without HIV likely play a dominant role in affecting TB bacterial burden. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R01AI147336. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Irvine, California and IRB of Botswana Ministry of Health and Wellness Human Research Development Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.