Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa

Subbarao, Sathyavani; Wilkinson, Katalin A.; Halsema, Clare L van; Rao, Suhasini Subba; Boyles, Tom; Utay, Netanya S.; Wilkinson, Robert J.; Meintjes, Graeme

doi:10.1097/qai.0000000000000763

Cited by 17 publications

(14 citation statements)

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“…Tuberculosis (TB) is the leading cause of hospitalization and in‐hospital death in human immunodeficiency virus (HIV)‐infected people worldwide . In high‐burden settings hospitalized patients with HIV‐associated TB (HIV‐TB) have case fatality rates between 11 and 32% . The majority of these deaths occur within 2 weeks and in postmortem series inpatient HIV‐TB deaths are reported at a median of 4–5 days after admission, with 50% of deaths occurring in patients already on anti‐TB therapy …”

Section: Introductionmentioning

confidence: 99%

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Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

Schutz

Chirehwa

Barr

et al. 2020

Brit J Clinical Pharma

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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 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). 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 anti-TB therapy. Twelve-week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed.Results: Pharmacokinetic 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 [C max ]: 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 C max 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 . Conclusion:Mortality 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 C max 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.The authors confirm that the PI for this paper is Graeme Meintjes and that he had direct clinical responsibility for patients. 966Br J Clin Pharmacol. 2020;86:966-978. wileyonlinelibrary.com/journal/bcp SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of this article. How to cite this article: Schutz C, Chirehwa M, Barr D, et al. Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus-associated tuberculosis. Br J Clin Pharmacol. 2020;86:966-978. https://doi.

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Section: Introductionmentioning

confidence: 99%

“…Limited existing data suggest that anti‐TB drug exposure in critically ill patients is inadequate . Elevated blood lactate is used as a marker of sepsis severity and is associated with mortality in hospitalized patients with HIV‐TB …”

Section: Introductionmentioning

confidence: 99%

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

Schutz

Chirehwa

Barr

et al. 2020

Brit J Clinical Pharma

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“…Consequently, nearly half of the HIV-associated disseminated TB observed in post-mortem studies was undiagnosed prior to death 4 . Even when disseminated TB is diagnosed or treated empirically, there is substantial diagnostic delay and patients with such severe disease may not survive; the time from initiation of treatment to death is often only a few days, at which time culture conversion and mycobacterial suppression has not yet occurred, despite empiric therapy 17 , 18 .…”

Section: Introductionmentioning

confidence: 99%

Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays

Kerkhoff

Barr

Schutz

et al. 2017

Sci Rep

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HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3–6.4; and 2.4, 95%CI = 1.3–4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.

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“…(7, 8) Also, most studies assessing TB burden among those with PLHIV used secondary data generated during routine service delivery, making disease burden quantification less reliable. (7–10). …”

Section: Introductionmentioning

confidence: 99%

Factors associated with mortality of TB/HIV co-infected patients in Ethiopia

Teklu¹,

Nega²,

Mamuye³

et al. 2017

Ethiop J Health Sci

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Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 17 publications

References 30 publications

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays

Factors associated with mortality of TB/HIV co-infected patients in Ethiopia

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