Improving the Diagnosis and Treatment of HIV-associated Tuberculous Meningitis

HIV-1 has caused a marked shift in the epidemiology of meningitis in sub-Saharan Africa and Mycobacterium tuberculosis is now a leading cause of meningitis in adults. Diagnosis of tuberculous meningitis (TBM) is notoriously difficult, compounded by an atypical cerebrospinal (CSF) picture in HIV co-infection. The WHO-recommended standard quadruple TB therapy may not be the optimal regimen in TBM as rifampicin does not readily penetrate into the CSF at the current dose. Better diagnostics and treatments are needed to tackle the disconcertingly high TBM mortality of at least 50% in people living with HIV (PLHIV). The goals of this PhD thesis were to first identify improved approaches to the diagnosis of TBM; and second, to investigate the safety and pharmacokinetics of a novel approach to treatment with high-dose rifampicin through a phase II open-label randomised controlled trial in predominantly HIV-positive adults. To begin, using retrospective data from two Ugandan referral hospitals, I showed that the introduction of the Cepheid Xpert MTB/Rif assay had markedly increased the microbiological confirmation of TBM. However, around half of TBM cases were treated on the basis of clinical suspicion alone, despite negative CSF TB tests. So, better diagnostics were still needed. I went on to examine the novel Xpert Ultra assay in a prospective diagnostic accuracy study, and found it to be the best CSF test for TBM, with a sensitivity of 77% and a negative predictive value of 93% for probable/ definite TBM, significantly better than Xpert MTB/Rif. A high CSF lactate and low CSF glucose were good discriminators of definite TBM. Given that CSF collection can be delayed or contraindicated, a non-CSF dependent test would be valuable, so i explored the potential of urine TB testing. Urine TBlipoarabinomannan (Alere LAM) and/or urine Xpert Ultra were positive in 50% of probable/definite TBM cases, suggesting extra-meningeal disseminated TB disease is highly prevalent in adults with HIV/TBM. In this exploratory study urine Xpert Ultra had prognostic value in definite TBM. The phase II randomised clinical trial demonstrated that with WHO-recommended TB treatment (containing rifampicin 10 mg/kg/day), CSF rifampicin was undetectable (