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

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dc.contributor.authorCresswell, Fiona V.
dc.contributor.authorMeya, David B.
dc.contributor.authorKagimu, Enock
dc.contributor.authorGrint, Daniel
dc.contributor.authorBrake, Lindsey te
dc.contributor.authorKasibante, John
dc.contributor.authorMartyn, Emily
dc.contributor.authorRutakingirwa, Morris
dc.contributor.authorQuinn, Carson M.
dc.contributor.authorOkirwoth, Micheal
dc.contributor.authorTugume, Lillian
dc.contributor.authorSsembambulidde, Kenneth
dc.contributor.authorMusubire, Abdu K.
dc.contributor.authorBangdiwala, Ananta S.
dc.contributor.authorBuzibye, Allan
dc.contributor.authorMuzoora, Conrad
dc.contributor.authorSvensson, Elin M.
dc.contributor.authorAarnoutse, Rob
dc.contributor.authorBoulware, David R.
dc.contributor.authorElliott, Alison M.
dc.date.accessioned2023-03-03T17:42:02Z
dc.date.available2023-03-03T17:42:02Z
dc.date.issued2021
dc.description.abstractHigh-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.en_US
dc.identifier.citationCresswell, F. V., Meya, D. B., Kagimu, E., Grint, D., Te Brake, L., Kasibante, J., ... & Elliott, A. 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), 876-884. DOI: 10.1093/cid/ciab162en_US
dc.identifier.other10.1093/cid/ciab162
dc.identifier.urihttps://nru.uncst.go.ug/handle/123456789/8067
dc.language.isoenen_US
dc.publisherClinical Infectious Diseasesen_US
dc.subjectTuberculous meningitisen_US
dc.subjectRifampicinen_US
dc.subjectIntensified therapyen_US
dc.subjectHIVen_US
dc.subjectTBMen_US
dc.titleHigh-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 Trialen_US
dc.typeArticleen_US
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