Abstract summary 

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. 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. NCT03927313 (25/04/2019).

Authors & Co-authors:  Davis Angharad G AG Wasserman Sean S Maxebengula Mpumi M Stek Cari C Bremer Marise M Daroowala Remy R Aziz Saalikha S Goliath Rene R Stegmann Stephani S Koekemoer Sonya S Jackson Amanda A Lai Sai Louise L Kadernani Yakub Y Sihoyiya Thandi T Liang C Jason CJ Dodd Lori L Denti Paolo P Crede Thomas T Naude Jonathan J Szymanski Patryk P Vallie Yakoob Y Banderker Ismail I Moosa Shiraz S Raubenheimer Peter P Lai Rachel P J RPJ Joska John J Nightingale Sam S Dreyer Anna A Wahl Gerda G Offiah Curtis C Vorster Isak I Candy Sally S Robertson Frances F Meintjes Ernesta E Maartens Gary G Black John J Meintjes Graeme G Wilkinson Robert J RJ

Study Outcome 

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