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@article{Davis:2023:cid/ciac932,
author = {Davis, AG and Wasserman, S and Stek, C and Maxebengula, M and Liang, CJ and Stegmann, S and Koekemoer, S and Jackson, A and Kadernani, Y and Bremer, M and Daroowala, R and Aziz, S and Goliath, R and Lai, Sai L and Sihoyiya, T and Denti, P and Lai, RPJ and Crede, T and Naude, J and Szymanski, P and Vallie, Y and Banderker, IA and Moosa, MS and Raubenheimer, P and Candy, S and Offiah, C and Wahl, G and Vorster, I and Maartens, G and Black, J and Meintjes, G and Wilkinson, RJ},
doi = {cid/ciac932},
journal = {Clinical Infectious Diseases},
pages = {1412--1422},
title = {A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus-associated tuberculous meningitis: the LASER-TBM trial},
url = {http://dx.doi.org/10.1093/cid/ciac932},
volume = {76},
year = {2023}
}

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TY  - JOUR
AB  - Background:Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design.Methods:We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35mg/kg/d] + linezolid 1200mg/d reducing after 28 days to 600mg/d; 3, as per arm 2 + aspirin 1000mg/d) for 56days, when the primary outcome of adverse events of special interest (AESI) or death was assessed.Results:A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan–Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms.Conclusions:High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.Clinical Trials Registration:NCT03927313.
AU  - Davis,AG
AU  - Wasserman,S
AU  - Stek,C
AU  - Maxebengula,M
AU  - Liang,CJ
AU  - Stegmann,S
AU  - Koekemoer,S
AU  - Jackson,A
AU  - Kadernani,Y
AU  - Bremer,M
AU  - Daroowala,R
AU  - Aziz,S
AU  - Goliath,R
AU  - Lai,Sai L
AU  - Sihoyiya,T
AU  - Denti,P
AU  - Lai,RPJ
AU  - Crede,T
AU  - Naude,J
AU  - Szymanski,P
AU  - Vallie,Y
AU  - Banderker,IA
AU  - Moosa,MS
AU  - Raubenheimer,P
AU  - Candy,S
AU  - Offiah,C
AU  - Wahl,G
AU  - Vorster,I
AU  - Maartens,G
AU  - Black,J
AU  - Meintjes,G
AU  - Wilkinson,RJ
DO  - cid/ciac932
EP  - 1422
PY  - 2023///
SN  - 1058-4838
SP  - 1412
TI  - A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus-associated tuberculous meningitis: the LASER-TBM trial
T2  - Clinical Infectious Diseases
UR  - http://dx.doi.org/10.1093/cid/ciac932
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000919802400001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://academic.oup.com/cid/article/76/8/1412/6884164
UR  - http://hdl.handle.net/10044/1/102146
VL  - 76
ER  -

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