Abstract
Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).
Highlights
In Africa human immunodeficiency virus (HIV)-1 associated tuberculous meningitis (TBM) has a 2-month mortality approaching 50%1
Early antiretroviral therapy (ART) is of proven benefit in other forms of tuberculosis (TB)[2] this has not been demonstrated for TBM3, a finding potentially contributed to by exacerbated immunopathology in the confined space of the central nervous system (CNS)[4]
Two published studies have investigated its potential role in TBM; the first, an observational study demonstrated favorable clinical outcomes and a non-significant difference in adverse events in children with drug sensitive TBM treated with LZD compared to control[13]; the second, a retrospective cohort study of 33 adults with TBM found that the addition of LZD to a standard regimen led to more rapid improvement in cerebrospinal fluid (CSF) parameters, recovery of consciousness and reduction of fever[14]
Summary
In Africa HIV-1 associated tuberculous meningitis (TBM) has a 2-month mortality approaching 50%1. In a placebo-controlled trial of ASA in 118 adult patients with TBM in India, 150mg daily ASA was associated with a significantly lower 3-month mortality and a lower incidence of stroke albeit not significant[20] Following this a similar study in South Africa randomized 146 children with TBM to receive low dose (75mg/24hours) (n=47) or high dose (1000mg/24 hours). In 2013 an open-labelled randomized phase 2 study in 60 Indonesian adults with TBM showed a 50% reduction in mortality with higher dose intravenous RIF (13 mg/kg, which equates to an approximate oral dose of 20mg/kg) compared with standard dose oral therapy[33] This intensified treatment did not result in increased toxicity and was associated with a substantially lower 6-month mortality. Our primary hypothesis is that increased dose RIF plus LZD and ASA can be safely added to standard therapy for HIV-1-associated TBM
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