Safety and tolerability of adjunctive linezolid with high or standard dose rifampin for the treatment of adults with HIV-associated tuberculous meningitis in Uganda: preliminary findings from the ALTER trial (S25.003)

Abstract

<h3>Objective:</h3> To analyze preliminary safety data from the <b>A</b>djunctive <b>L</b>inezolid for the <b>T</b>reatment of Tub<b>ER</b>culous Meningitis (ALTER) trial, a phase II trial of high or standard-dose rifampin with or without linezolid 1200 mg for the first 4 weeks of treatment on a backbone of isoniazid, pyrazinamide, and ethambutol. <h3>Background:</h3> Better treatments are needed for tuberculous meningitis (TBM), which leads to mortality in excess of 50%. Linezolid penetrates into cerebrospinal fluid and is effective against TB. Little is known about its use in often critically ill TBM patients. <h3>Design/Methods:</h3> Persons with HIV (PWH) with definite or suspected TBM were recruited from a rural hospital in southwestern Uganda. Participants were seen on day 2, weeks 1, 2, 4, 8, 12, 18, and 24 for symptom assessment, medication adherence, physical examination, visual testing, neuropathy screening, and/or safety labs. <h3>Results:</h3> Of 23 participants enrolled (52% women, mean age 37 years, 78% with moderate to severe TBM grade), 12 were allocated to linezolid. Median CD4 count was 150 cells/mm³, (IQR 81–331) and 7 were on anti-retroviral therapy (ART). Twelve serious adverse events (SAEs) occurred, 6 among those on linezolid. The six included, sepsis (n=2), aspiration pneumonia (n=1), ART-related Stevens-Johnson syndrome (n=1), dehydration (n=1), and hyponatremia (n=1). Seven participants died, 2 on linezolid. No SAE was determined to be related to linezolid. No participants required linezolid discontinuation or dose reduction. Three participants developed ≥grade 3 hyponatremia. No ≥grade 3 anemia, thrombocytopenia, or neutropenia occurred. Mild grade 1 or 2 neuropathy symptoms were reported, more commonly among linezolid recipients (55% versus 0%, p=0.025), but resolved after treatment ended. <h3>Conclusions:</h3> In this preliminary analysis, linezolid was generally safe and well tolerated in TBM patients. Data from the completed trial will increase the power to determine if linezolid is safe to use with high and standard dose rifampin in PWH and TBM. <b>Disclosure:</b> Dr. Kibengo has nothing to disclose. Dr. Kabarambi has nothing to disclose. Mr. Kafeero has nothing to disclose. Dr. Patrick has nothing to disclose. Dr. NAKIMBUGWE has nothing to disclose. Mr. Ssemaganda has nothing to disclose. Mr. Tayebwa has nothing to disclose. The institution of Dr. Nahid has received research support from NIH . The institution of Fiona Cresswell has received research support from Janssen. Dr. Chow has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Medicolegal consulting. The institution of Dr. Chow has received research support from NIH.