Abstract
AimsPatients 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 anti‐TB 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).MethodsWe 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 anti‐TB therapy. Twelve‐week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed.ResultsPharmacokinetic data were collected in 59 hospitalized HIV‐TB patients and 48 outpatients. Inpatient 12‐week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (maximum concentration [Cmax]: 7.4 vs 8.3 μg mL–1, P = .223; 3.6 vs 3.5 μg mL–1, P = .569; 50.1 vs 46.8 μg mL–1, P = .081; area under the concentration–time curve from 0 to 8 hours: 41.0 vs 43.8 mg h L–1, P = 0.290; 13.5 vs 12.4 mg h L–1, P = .630; 316.5 vs 292.2 mg h L–1, P = .164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid Cmax were below recommended ranges in 61% and 39% of inpatients and 44% and 35% of outpatients. Rifampicin exposure was higher in patients with lactate >2.2 mmol L–1.ConclusionMortality in hospitalized HIV‐TB patients was high. Early anti‐TB drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid Cmax were suboptimal 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.
Highlights
Tuberculosis (TB) is the leading cause of hospitalization and inhospital death in human immunodeficiency virus (HIV)-infected people worldwide.[1,2] In high-burden settings hospitalized patients with HIV-associated TB (HIV-TB) have case fatality rates between 11 and 32%.3-8 The majority of these deaths occur within 2 weeks[3-5,8] and in postmortem series inpatient HIV-TB deaths are reported at a median of 4–5 days after admission[9,10], with 50% of deaths occurring in patients already on anti-TB therapy.[11]Severe HIV-TB may present with clinical features of bacterial sepsis.[12-14]
We found high 12-week mortality of 19% for inpatients and no significant difference in Cmax or AUC0–8 of rifampicin, isoniazid or pyrazinamide between hospitalized patients and outpatients, or between hospitalized patients who survived and those who died
Rifampicin and isoniazid peak concentrations were below reference ranges in 61% and 39% of inpatients and 44% and 35% of outpatients
Summary
Tuberculosis (TB) is the leading cause of hospitalization and inhospital death in human immunodeficiency virus (HIV)-infected people worldwide.[1,2] In high-burden settings hospitalized patients with HIV-associated TB (HIV-TB) have case fatality rates between 11 and 32%.3-8 The majority of these deaths occur within 2 weeks[3-5,8] and in postmortem series inpatient HIV-TB deaths are reported at a median of 4–5 days after admission[9,10], with 50% of deaths occurring in patients already on anti-TB therapy.[11]Severe HIV-TB may present with clinical features of bacterial sepsis.[12-14]. In high-burden settings hospitalized patients with HIV-associated TB (HIV-TB) have case fatality rates between 11 and 32%.3-8. The majority of these deaths occur within 2 weeks[3-5,8] and in postmortem series inpatient HIV-TB deaths are reported at a median of 4–5 days after admission[9,10], with 50% of deaths occurring in patients already on anti-TB therapy.[11]. Severe HIV-TB may present with clinical features of bacterial sepsis.[12-14]. In high-burden settings Mycobacterium tuberculosis bloodstream infection is the most common diagnosis in HIV-infected patients presenting to hospital with a clinical syndrome of sepsis.[15-18]. Other factors in advanced HIV infection such as intestinal TB, HIV-related enteropathy, and gastrointestinal opportunistic infections and macroor micronutrient deficiencies[21-23] could contribute to reduced drug exposure. Elevated blood lactate is used as a marker of sepsis severity[25] and is associated with mortality in hospitalized patients with HIV-TB.[5]
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