The Francis Crick Institute
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Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus-associated tuberculosis.

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journal contribution
posted on 2020-05-04, 13:05 authored by Charlotte Schutz, Maxwell Chirehwa, David Barr, Amy Ward, Saskia Janssen, Rosie Burton, Robert J Wilkinson, Muki Shey, Lubbe Wiesner, Paolo Denti, Helen McIlleron, Gary Maartens, Graeme Meintjes
AIMS: Patients hospitalized at the time of human immunodeficiency virus-associated tuberculosis (HIV-TB) diagnosis have high early mortality. We hypothesized that compared to outpatients, there would be lower antituberculosis drug exposure in hospitalized HIV-TB patients, and amongst hospitalized patients exposure would be lower in patients who die or have high lactate (a sepsis marker). METHODS: We performed pharmacokinetic sampling in hospitalized HIV-TB patients and outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations were measured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the third day of standard antituberculosis therapy. Twelve-week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Pharmacokinetic data was collected in 59 hospitalized HIV-TB patients and 48 outpatients. Inpatient twelve-week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (Cmax :7.4 vs. 8.3 μg·mL-1 , p=0.223; 3.6 vs. 3.5 μg·mL-1 , p=0.569; 50.1 vs. 46.8 μg·mL-1 , p=0.081; AUC0-8 :41.0 vs. 43.8 mg·h·L-1 , p= 0.290; 13.5 vs. 12.4 mg·h·L-1 , p=0.630; 316.5 vs. 292.2 mg·h·L-1 , p=0.164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid Cmax were below recommended ranges in 61% and 39% inpatients and 44% and 35% outpatients. Rifampicin exposure was higher in patients with lactate >2.2mmol·L-1 . CONCLUSION: Mortality in hospitalized HIV-TB patients was high. Early antituberculosis drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid Cmax were sub-optimal in 61% and 39% of inpatients and rifampicin exposure was higher in patients with high lactate. Treatment strategies need to be optimized to improve survival.


Crick (Grant ID: 10218, Grant title: Wilkinson, R FC001218)