High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly Human Immunodeficiency Virus (HIV)-positive Ugandan adults: a phase II open-label randomized controlled trial

Cresswell, Fiona V, Meya, David B, Kagimu, Enock, Grint, Daniel, Te Brake, Lindsey, Kasibante, John, Martyn, Emily, Rutakingirwa, Morris, Quinn, Carson M, Okirwoth, Micheal, Tugume, Lillian, Ssembambulidde, Kenneth, Musubire, Abdu K, Bangdiwala, Ananta S, Buzibye, Allan, Muzoora, Conrad, Svensson, Elin M, Aarnoutse, Rob, Boulware, David R and Elliott, Alison M (2021) High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly Human Immunodeficiency Virus (HIV)-positive Ugandan adults: a phase II open-label randomized controlled trial. Clinical Infectious Diseases, 73 (5). pp. 876-884. ISSN 1058-4838

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Abstract

Background
High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity.

Methods
In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0–24), maximum concentration (Cmax), CSF concentration, and grade 3–5 adverse events.

Results
We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC0–24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0–24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2–2.5) for IV-20 and 2.17 mg/L (1.6–2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34).

Conclusions
Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC.

Item Type: Article
Keywords: HIV, TBM, intensified therapy, rifampicin, tuberculous meningitis, Adult, Antitubercular Agents, HIV, HIV Infections, Humans, Rifampin, Tuberculosis, Meningeal, Uganda
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 27 May 2022 16:18
Last Modified: 27 May 2022 16:18
URI: http://sro.sussex.ac.uk/id/eprint/106149

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