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
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 73(2021), 5 vom: 07. Sept., Seite 876-884 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cresswell, Fiona V [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.09.2021 Date Revised 29.12.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciab162 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM322506220 |
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| 100 | 1 | |a Cresswell, Fiona V |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults |b A Phase II Open-Label Randomized Controlled Trial |
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| 500 | |a Date Completed 22.09.2021 | ||
| 500 | |a Date Revised 29.12.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a TBM | |
| 650 | 4 | |a intensified therapy | |
| 650 | 4 | |a rifampicin | |
| 650 | 4 | |a tuberculous meningitis | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Rifampin |2 NLM | |
| 650 | 7 | |a VJT6J7R4TR |2 NLM | |
| 700 | 1 | |a Meya, David B |e verfasserin |4 aut | |
| 700 | 1 | |a Kagimu, Enock |e verfasserin |4 aut | |
| 700 | 1 | |a Grint, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Te Brake, Lindsey |e verfasserin |4 aut | |
| 700 | 1 | |a Kasibante, John |e verfasserin |4 aut | |
| 700 | 1 | |a Martyn, Emily |e verfasserin |4 aut | |
| 700 | 1 | |a Rutakingirwa, Morris |e verfasserin |4 aut | |
| 700 | 1 | |a Quinn, Carson M |e verfasserin |4 aut | |
| 700 | 1 | |a Okirwoth, Micheal |e verfasserin |4 aut | |
| 700 | 1 | |a Tugume, Lillian |e verfasserin |4 aut | |
| 700 | 1 | |a Ssembambulidde, Kenneth |e verfasserin |4 aut | |
| 700 | 1 | |a Musubire, Abdu K |e verfasserin |4 aut | |
| 700 | 1 | |a Bangdiwala, Ananta S |e verfasserin |4 aut | |
| 700 | 1 | |a Buzibye, Allan |e verfasserin |4 aut | |
| 700 | 1 | |a Muzoora, Conrad |e verfasserin |4 aut | |
| 700 | 1 | |a Svensson, Elin M |e verfasserin |4 aut | |
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| 700 | 1 | |a Boulware, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Elliott, Alison M |e verfasserin |4 aut | |
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