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. (8th March 2021)

• Record Type: Journal Article
• Authors: 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; Elliott, Alison M
• Is Part Of: Clinical infectious diseases. Volume 73:Number 5(2021)
• Page Start: 876
• Page End: 884
• Publication Date: 2021-03-08
• Subjects: tuberculous meningitis -- rifampicin -- intensified therapy -- HIV -- TBM; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciab162
• Languages: English
• ISSNs: 1058-4838

Abstract

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. Abstract : Rifampicin is undetectable in the cerebrospinal fluid (CSF) of the majority of tuberculosis meningitis patients at standard dosing. Highdose rifampicin administered intravenously 20 mg/kg and orally 35 mg/kg resulted in therapeutic CSF rifampicin concentrations with no excess toxicity in a population consisting predominantly of people living with human immunodeficiency virus (HIV).