Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial

Abstract

Background Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs. Methods Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in ex vivo whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points. Results All PET/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in ex-vivo culture was enhanced by auranofin compared to controls, but not by other HDTs. Conclusions None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.

Antibiotics in the clinical pipeline as of December 2022

“…Dovramilast ( 42 ) is being evaluated in a phase-II trial (NCT03807362) at The Leprosy Mission Nepal (Katmandu, Nepal) for patients with erythema nodosum leprosum (ENL), which is an inflammatory disorder triggered by leprosy. Another phase-II trial (NCT02968927) run by The Aurum Institute NPC (Johannesburg, South Africa) has been completed [ 235 , 236 ]. PDE4 inhibitors are an adjunctive host-directed therapy designed to modulate the inflammatory response to Mtb infection by reducing, but not fully blocking, TNF-α production by the host cells.…”

Development and application of the direct mycobacterial growth inhibition assay: a systematic review

“…Further reports from the same group describe the assay applied to whole blood taken from different volunteer groups to study the survival and replication of clinical M.tb isolates or laboratory strains in the context of host innate immunity ( 23 ), and the control of different M.tb strains in blood from cured TB patients and tuberculin-negative volunteers ( 24 ). With respect to the screening of various TB drug therapies, Wallis and others have also reported on the effect of host-directed TB therapies ( 25 ), the activity of orally-administered clofazimine, PNU-100480 alone or with bedaquiline plus rifabutin or rifampicin ( 26 – 30 ), activity of faropenem with and without rifampicin ( 31 ), activity of sutezolid (PNU-100480) and its major metabolite ( 32 ), coadministration of allopurinol with pyrazinamide ( 33 ), and adjunctive use of celecoxib with anti-tuberculosis drugs ( 34 ).…”

“…Further reports from the same group describe the assay applied to whole blood taken from different volunteer groups to study the survival and replication of clinical M.tb isolates or laboratory strains in the context of host innate immunity (23), and the control of different M.tb strains in blood from cured TB patients and tuberculin-negative volunteers (24). With respect to the screening of various TB drug therapies, Wallis and others have also reported on the effect of host-directed TB therapies (25), the activity of orally-administered clofazimine, PNU-100480 alone or with…”

Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion

“…concentrations, phosphodiesterase 4A (PDE4A) expression in immune cells results in increased inflammatory mediator secretion and is the target of various FDA approved immune modulators [17]. In a pre-clinical animal model [18,19] and a recent human randomized clinical trial [20,21], PDE4 inhibition limited immunopathology and improved pulmonary function among subjects with TB. In contrast to a potentially detrimental effect at late timepoints, the expression of multiple PDE4A isoforms was higher among RSTR subjects immediately following ex vivo Mtb infection suggesting an early hyperinflammatory response may be protective for TST/IGRA conversion.…”