PhD upgrade | Improving diagnosis and treatment of HIV-associated TB meningitis

Summary

Tuberculous meningitis (TBM) is the second leading cause of adult meningitis in countries with high HIV prevalence, such as Uganda. Outcomes from TBM are poor, particularly in HIV co-infection which confers a 2 to 3-fold increased risk of death. One of the contributory factors is the lack of a rapid and reliable diagnostic test for TBM resulting in diagnostic delay. Another contributory factor is the imperfect penetration of anti-tuberculous therapy into the brain and cerebrospinal fluid (CSF).

A novel molecular assay Gene Xpert MTB/Rif Ultra (Ultra) that has an 8-fold lower limit of detection than the existing molecular assay Xpert MTB/Rif (Xpert) is on the horizon. Intensified treatment for TBM, both in terms of alternative drugs and increased doses of currently used anti-tuberculous agents, is receiving research attention in Asia, although there is currently no preliminary data from an African population.

The primary diagnostic hypothesis is that Ultra will be significantly more sensitive than existing tests (Xpert and culture) in the diagnosis of TBM; however, Ultra will miss a small number of cases that are detectable on post-mortem and next generation sequencing. The primary therapeutic hypothesis is the higher dose rifampicin given intravenously (20mg/kg) and orally (35mg/kg) will be safe and will provide significantly superior exposures in plasma and CSF than standard of care (10mg/kg); and this may result in improved clinical outcomes.

These hypotheses will be investigated through a prospective phase II randomised clinical trial in Uganda. Diagnostic lumbar punctures will be performed on 240 adults presenting with meningitis and CSF will undergo a comprehensive diagnostic battery. I will then enrol 60 adults into a three-arm randomised controlled trial (the RifT trial) evaluating the safety, pharmacokinetics and pharmacodynamics of high dose intravenous and oral rifampicin compared to standard of care.

Details

Speaker: Fiona Cresswell

Date: 3 May 2018

Time: 12:30 – 13:30

Venue: LG8, Keppel Street

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