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Background: Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized. Methods: We conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition. Results: Among 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV. Conclusions: LTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection. [ABSTRACT FROM AUTHOR]

Introduction: Host blood transcriptomic biomarkers have potential as rapid point-of-care triage, diagnostic, and predictive tests for Tuberculosis disease. We aimed to summarise the performance of host blood transcriptomic signatures for diagnosis of and prediction of progression to Tuberculosis disease; and compare their performance to the recommended World Health Organisation target product profile. Methods: A systematic review and meta-analysis of the performance of host blood mRNA signatures for diagnosing and predicting progression to Tuberculosis disease in HIV-negative adults and adolescents, in studies with an independent validation cohort. Medline, Scopus, Web of Science, and EBSCO libraries were searched for articles published between January 2005 and May 2019, complemented by a search of bibliographies. Study selection, data extraction and quality assessment were done independently by two reviewers. Meta-analysis was performed for signatures that were validated in ≥3 comparable cohorts, using a bivariate random effects model. Results: Twenty studies evaluating 25 signatures for diagnosis of or prediction of progression to TB disease in a total of 68 cohorts were included. Eighteen studies evaluated 24 signatures for TB diagnosis and 17 signatures met at least one TPP minimum performance criterion. Three diagnostic signatures were validated in clinically relevant cohorts to differentiate TB from other diseases, with pooled sensitivity 84%, 87% and 90% and pooled specificity 79%, 88% and 74%, respectively. Four studies evaluated signatures for progression to TB disease and performance of one signature, assessed within six months of TB diagnosis, met the minimal TPP for a predictive test for progression to TB disease. Conclusion: Host blood mRNA signatures hold promise as triage tests for TB. Further optimisation is needed if mRNA signatures are to be used as standalone diagnostic or predictive tests for therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Background: Adolescents in the Western Cape Province of South Africa had high force of Mycobacterium tuberculosis (MTB) infection (14% per annum) and high TB incidence (710 per 100,000 person–years) in 2005. We describe subsequent temporal changes in adolescent TB disease notification rates for the decade 2005–2015. Method: We conducted an analysis of patient–level adolescent (age 10–19 years) TB disease data, obtained from an electronic TB register in the Breede Valley sub–district, Western Cape Province, South Africa, for 2005–2015. Numerators were annual TB notifications (HIV–related and HIV–unrelated); denominators were mid–year population estimates. Period averages of TB rates were obtained using time series modeling. Temporal trends in TB rates were explored using the Mann–Kendall test. Findings: The average adolescent TB disease notification rate was 477 per 100,000 for all TB patients (all–TB) and 361 per 100,000 for microbiologically–confirmed patients. The adolescent all–TB rate declined by 45% from 662 to 361 per 100,000 and the microbiologically–confirmed TB rate by 38% from 492 to 305 per 100,000 between 2005–2015, driven mainly by rapid decreases for the period 2005–2009. There was a statistically significant negative temporal trend in both all–TB (per 100,000) (declined by 48%; from 662 to 343; p = 0·028) and microbiologically confirmed TB (per 100,000) (declined by 49%; from 492 to 252; p = 0·027) for 2005–2009, which was not observed for the period 2009–2015 (rose 5%; from 343 to 361; p = 0·764 and rose 21%; from 252 to 305; p = 1·000, respectively). Interpretation: We observed an encouraging fall in adolescent TB disease rates between 2005–2009 with a subsequent plateau during 2010–2015, suggesting that additional interventions are needed to sustain initial advances in TB control. [ABSTRACT FROM AUTHOR]