Research Spotlight

Posted November 15th 2016

Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Swaminathan, S., J. G. Pasipanodya, G. Ramachandran, A. K. Hemanth Kumar, S. Srivastava, D. Deshpande, E. Nuermberger and T. Gumbo (2016). “Drug concentration thresholds predictive of therapy failure and death in children with tuberculosis: Bread crumb trails in random forests.” Clin Infect Dis 63(suppl 3): S63-s74.

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BACKGROUND: The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS: Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables. RESULTS: Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L x hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82). CONCLUSIONS: We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.


Posted November 15th 2016

Isoniazid clearance is impaired among HIV/tuberculosis patients with high levels of immune activation.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Vinnard, C., S. Ravimohan, N. Tamuhla, V. Ivaturi, J. Pasipanodya, S. Srivastava, C. Modongo, N. M. Zetola, D. Weissman, T. Gumbo and G. P. Bisson (2016). “Isoniazid clearance is impaired among hiv/tuberculosis patients with high levels of immune activation.” Br J Clin Pharmacol: 2016 Oct [Epub ahead of print].

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AIMS: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating ART would be associated with impaired clearance of isoniazid. METHODS: We conducted a prospective observational study of isoniazid pharmacokinetics and systemic immune activation prior to and one month after antiretroviral therapy (ART) initiation. Non-linear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N-acetyltransferase-2 (NAT-2) genotype and inter-occasional variability on clearance (thereby analyzing the pharmacokinetic data before and after ART initiation in a single model). RESULTS: We enrolled 40 patients in the pharmacokinetic visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a 2-compartment model with first-order elimination. After accounting for NAT-2 genotype, increasing levels of CD38 and HLA-DR expression on CD8+ T cells (CD38+ DR+ CD8+ ) were associated with decreasing isoniazid clearance. CONCLUSION: HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.


Posted November 15th 2016

Intensive Hemodialysis, Blood Pressure, and Antihypertensive Medication Use.

Peter McCullough M.D.

Peter McCullough M.D.

Bakris, G. L., J. M. Burkart, E. D. Weinhandl, P. A. McCullough and M. A. Kraus (2016). “Intensive hemodialysis, blood pressure, and antihypertensive medication use.” Am J Kidney Dis 68(5s1): S15-s23.

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Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is >85% in new patients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure (SBP) is nearly 150mmHg, and about 70%, 50%, and 40% use beta-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multifactorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain, particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the short daily schedule reduced predialysis SBP by 7.7mmHg, whereas the nocturnal schedule reduced predialysis SBP by 7.3mmHg, both relative to 3 sessions per week. Improvements were sustained after 12 months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepinephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the need for antihypertensive medications.


Posted November 15th 2016

Intensive Hemodialysis, Mineral and Bone Disorder, and Phosphate Binder Use.

Peter McCullough M.D.

Peter McCullough M.D.

Copland, M., P. Komenda, E. D. Weinhandl, P. A. McCullough and J. A. Morfin (2016). “Intensive hemodialysis, mineral and bone disorder, and phosphate binder use.” Am J Kidney Dis 68(5s1): S24-s32.

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Mineral and bone disorder is a common complication of end-stage renal disease. Notably, hyperphosphatemia likely promotes calcification of the myocardium, valves, and arteries. Hyperphosphatemia is associated with higher risk for cardiovascular mortality and morbidity along a gradient beginning at 5.0mg/dL. Among contemporary hemodialysis (HD) patients, mean serum phosphorus level is 5.2mg/dL, although 25% of patients have serum phosphorus levels of 5.5 to 6.9mg/dL; and 13%, >7.0mg/dL. Treatment of hyperphosphatemia is burdensome. Dialysis patients consume a mean of 19 pills per day, half of which are phosphate binders. Medicare Part D expenditures on binders for dialysis patients approached $700 million in 2013. Phosphorus removal with thrice-weekly HD (4 hours per session) is approximately 3,000mg/wk. However, clearance is unlikely to counterbalance dietary intake, which varies around a mean of 7,000mg/wk. Dietary restriction and phosphate binders are important interventions, but each has limitations. Dietary control is complicated by limited access to healthy food choices and unclear labeling. Meanwhile, adherence to phosphate binders is poor, especially in younger patients and those with high pill burden. Multiple randomized clinical trials show that intensive HD reduces serum phosphorus levels. In the Frequent Hemodialysis Network (FHN) trial, short daily and nocturnal schedules reduced serum phosphorus levels by 0.6 and 1.6mg/dL, respectively, relative to 3 sessions per week. A similar effect of nocturnal HD was observed in an earlier trial. In the daily arm of the FHN trial, intensive HD significantly lowered estimated phosphate binder dose per day, whereas in the nocturnal arm, intensive HD led to binder discontinuation in 75% of patients. However, intensive HD appears to have no meaningful effects on serum calcium and parathyroid hormone concentrations. In conclusion, intensive HD, especially nocturnal HD, lowers serum phosphorus levels and decreases the need for phosphate binders.


Posted November 15th 2016

Intensive Hemodialysis, Left Ventricular Hypertrophy, and Cardiovascular Disease.

Peter McCullough M.D.

Peter McCullough M.D.

McCullough, P. A., C. T. Chan, E. D. Weinhandl, J. M. Burkart and G. L. Bakris (2016). “Intensive hemodialysis, left ventricular hypertrophy, and cardiovascular disease.” Am J Kidney Dis 68(5s1): S5-s14.

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The prevalence of cardiovascular disease, including cardiac arrhythmia, coronary artery disease, cardiomyopathy, and valvular heart disease, is higher in hemodialysis (HD) patients than in the US resident population. Cardiovascular disease is the leading cause of death in HD patients and the principal discharge diagnosis accompanying 1 in 4 hospital admissions. Furthermore, the rate of hospital admissions for either heart failure or fluid overload is persistently high despite widespread use of beta-blockers and renin-angiotensin system inhibitors and attempts to manage fluid overload with ultrafiltration. An important predictor of cardiovascular mortality and morbidity in dialysis patients is left ventricular hypertrophy (LVH). LVH is an adaptive response to increased cardiac work, typically caused by combined pressure and volume overload, resulting in cardiomyocyte hypertrophy and increased intercellular matrix. In new dialysis patients, the prevalence of LVH is 75%. Regression of LVH may reduce cardiovascular risk, including the incidence of heart failure, complications after myocardial infarction, and sudden arrhythmic death. Multiple randomized clinical trials show that intensive HD reduces left ventricular mass, a measure of LVH. Short daily and nocturnal schedules in the Frequent Hemodialysis Network trial reduced left ventricular mass by 14 (10%) and 11 (8%) g, respectively, relative to 3 sessions per week. Comparable efficacy was observed in an earlier trial of nocturnal HD. Intensive HD also improves cardiac rhythm. Clinical benefits have been reported only in observational studies. Daily home HD is associated with 17% and 16% lower risks for cardiovascular death and hospitalization, respectively; admissions for cerebrovascular disease, heart failure, and hypertensive disease, which collectively constitute around half of cardiovascular hospitalizations, were less likely with daily home HD. Relative to peritoneal dialysis, daily home HD is likewise associated with lower risk for cardiovascular hospitalization. In conclusion, intensive HD likely reduces left ventricular mass and may lead to lower risks for adverse cardiac events.