DISCUSSION
TB, death, bleeding, decreased consciousness, HIV-associated TBM, disability, TBM
DISEASE, EVENTS, SECONDARY, BLEEDING
LASER-TBM was a phase 2A RCT that evaluated the safety of high-dose rifampicin (35 mg/kg daily), adjunctive linezolid, and high-dose aspirin for the first 56 days of treatment in HIV-associated TBM. Primary end point analysis showed no significant difference in the incidence of AESI or death between treatment arms. There was no difference in death or disability at day 56 across arms, and a similar frequency of clinical or radiological events occurred in each arm.Although secondary analysis revealed a significantly higher number of events (AESI or death) in arm 3 vs arm 1 (There are limitations to this study. Although no formal power calculation took place, sample size was smaller than the target of 100 participants. It is unknown whether the significantly higher number of AESI or death in arm 3 vs arm 1 demonstrated within the secondary analysis reflects a true safety risk of the regimen containing aspirin or is due to chance given the smaller sample size. Second, the majority participants recruited had mild TBM. The reasons for this are multiple including patients dying prior to screening (because 5 days of TB treatment was allowed prior to enrollment) and patients with decreased consciousness arriving at the hospital alone without available next of kin available for proxy consent. In the latter case, a protocol amendment allowed deferred consent for these patients, which is likely to explain in part the higher rate of mild disease in our cohort. The mild disease within our patient cohort likely explains the low level of mortality; 16% 2-month mortality contrasted with the often-quoted 50% mortality in the literature [Our study, the first RCT to evaluate linezolid in TBM, demonstrates that this important drug can be safely added to standard of care to treat HIV-associated TBM. It is also the first study to date to systematically evaluate the safety of a novel drug regimen that contains enhanced antitubercular treatments alongside a host-directed therapy in TBM, demonstrating that this approach can be safe. Our results show that high-dose rifampicin and linezolid may be safely combined in HIV-associated TBM and support evaluation of the efficacy of these drugs either alone or in combination in phase 3 trials. Within our study, we did not see any significant bleeding events with the use of high-dose aspirin. A larger study is now required to see if potential harm is offset by a morbidity and mortality benefit.