academic.oup.com
Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis
Host immune responses to HIV-associated cryptococcal meningitis are thought to play critical roles in disease outcome, yet their interaction with antifungal drug exposure is poorly understood. This study explored the relative associations between immune biomarkers, antifungal drug exposure, and clinical outcomes in HIV-associated cryptococcal meningitis.MethodsWe analyzed plasma and cerebrospinal fluid (CSF) immune biomarkers from 64 participants recruited from the AMBITION-cm trial on days 1, 7 and 14 of antifungal therapy. We estimated individual-level exposure to amphotericin B, flucytosine and fluconazole using non-parametric pharmacokinetic modelling. Principal component analysis (PCA) and network analysis were used to reduce the dimensionality of the dataset of immune biomarkers. Associations between immune biomarkers, PK parameters, and clinical outcomes of fungal burden, opening lumbar pressure, early fungicidal activity (EFA), and 10-week mortality were evaluated.ResultsAn inflammatory CSF response, characterised by coordination between TNF-α, G-CSF and IL-7 signalling, was linked to low fungal burden, low intracranial pressure, and survival. However, neither the value of specific immune biomarkers nor their change over time strongly predicted EFA or mortality. Exposure to amphotericin B was significantly associated with EFA.ConclusionsOur results suggest that favourable clinical outcomes from HIV-associated cryptococcal meningitis are associated with coordinated inflammatory and cytotoxic responses in the CNS. Plasma immune signatures were less consistent in our dataset. There was a notable lack of dynamism in immune biomarkers over time. In terms of interventions, the most convincing evidence is for optimisation of antifungal drug exposure, which was the dominant predictor of EFA.
