Background
The risk of progression from Mycobacterium tuberculosis (Mtb) infection to active TB disease is estimated to be up to 20 times higher in people living with HIV (PLWH), with fatality rates of 16 – 35%. We have previously shown that blood transcriptional biomarkers can predict risk of TB progression in PLWH. We use transcriptional TB risk scores to explore risk of TB associated with HIV in a unique acute infection cohort of PLWH with longitudinal sample collection before and after HIV acquisition
Methods
We utilized stored whole blood collected in RNAlater from the MERLIN cohort: a longitudinal cohort of transgender women and men who have sex with men. Uninfected participants were followed from 2013-2016 with monthly testing for HIV; 216 participants with acute or recent HIV infection (by serology or RNA) and a documented HIV-negative test within 90 days were enrolled and randomized to begin ART immediately or to defer for 6 months. Participants (~50%) have remained in follow up with viral suppression for 8-10 years after ART initiation. We sequenced RNA from two pre-HIV samples (enrolment and last sample before diagnosis), at the first post-diagnosis timepoint, months 3, 6, 12, 24, and 48 after HIV diagnosis. TB risk scores were calculated at each timepoint using the Risk6 TB signature that we previously developed, consisting of three upregulated and three downregulated genes. The risk scores were computed as follows: geometric mean of log2 (GMlog2) counts of upregulated genes – GMlog2 counts of downregulated genes
Results
Prior to HIV infection, there was no difference in TB risk between enrollment and last timepoint before HIV-infection. TB risk increased at diagnosis (p<0.0001), and then decreased by month 3 (p = 0.0008) and month 6 (p<0.0001). At six months after diagnosis, TB risk scores had decreased to enrollment (baseline) levels in both the immediate (treated) and deferred (untreated) arms.
Conclusions
TB risk increased soon after HIV acquisition. Our preliminary data suggests that the risk decreases in PLWH who show at least some virologic control, as scores decreased at 6 months even in untreated participants. We previously showed that TB risk scores (derived from interferon inducible genes) are associated with viremia, suggesting viremia contributes to the signature. Thus, decrease in TB risk scores may reflect VL reductions due to treatment or progression to set point in untreated participants