Degree of plasma protein binding affects central nervous system (CNS) free drug penetration for the HIV-1 protease inhibitors among patients in an urban HIV clinic. Público

Abstract

Background: High prevalence of HIV-1 associated neurocognitive disorders (HAND) persists in the highly active antiretroviral therapy (HAART) era. For optimal antiviral effect, adequate antiretroviral penetration into the central nervous system (CNS) is needed. HIV protease inhibitors' (PI) CNS concentration may be limited by high level of plasma protein blinding, as only unbound drug crosses the blood-brain barrier easily. Atazanavir (ATV) and Darunavir (DRV), two prescribed PIs, differ in degree of plasma protein binding, 86% and 95%, respectively, and cerebrospinal fluid (CSF):plasma free drug ratio should be higher for ATV.

Objectives: The primary objective was to compare the CNS penetration, as measured by free drug CSF:plasma trough concentration ratios, between ATV and DRV. Relationships between PI free CSF concentrations and CSF HIV-1 RNA and CSF neopterin were assessed.

Methods: In a cross-sectional study conducted among virologically suppressed adult HIV-infected individuals receiving tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) + ritonavir (RTV)-boosted once daily ATV or DRV for > 6 months, paired CSF and plasma was collected at trough times. Free PI concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured using Ampliprep/COBAS^® Taqman^® 2.0 assay (Roche) and enzyme linked immunosorbent assay (ALPCO), respectively.

Results: Thirty subjects (15 per arm) were enrolled. Demographics and comorbidities were comparable between arms. All subjects had normal renal and liver function. CSF: plasma free drug ratio was higher for ATV compared to DRV, 0.38 (95% CL 0.20-0.56) vs 0.065 (95% CL 0.043-0.087), p<0.0001. CSF free drug concentrations exceeded protein adjusted wild-type IC50 for 13 of 15 subjects in each arm. 13% (2/15) and 26.7% (4/15) in the ATV and DRV arms had detectable (>40 copies/mL) CSF HIV-1 RNA, p = 0.65. Mean (95% CL) CSF neopterin levels were within normal range, 1.76 ng/mL(1.38-2.13) for ATV and 1.73 ng/mL (1.53-1.92) for DRV, p =0.88.

Conclusions: Higher CSF:plasma free ATV concentration ratio relative to DRV is likely due to lower ATV protein binding. CSF free drug concentrations were not associated with CSF HIV-1 RNA or neopterin, implying that multiple factors play roles in controlling CNS viremia and inflammation.

Table of Contents

Introduction 1-2

Background 3-6

Methods 7-14

Results 15-18

Discussion 19-22

References 23-25

Figure 1: Summary of recruitment and enrollment for

Atazanavir and Darunavir arms 26

Table 1: Demographic and clinic characteristics at enrollment 27

Table 2: Laboratory findings within 90 days of enrollment 28

Table 3: Comorbidities and past medical history 29

Table 4: Timing of plasma and cerebrospinal fluid (CSF) collection 30

Table 5: Plasma and CSF sampling results stratified by arm 31

Table 6: Plasma and CSF sampling for patients with detectable

CSF HIV-1 RNA 32

Table 7: Plasma and CSF sampling of patients with CSF free protease

inhibitor concentrations not exceeding drug-specific IC50 33

Figure 2: Log free CSF:plasma drug concentration ratio compared by arm 34

Table 8 : Univariate analysis using linear regression for determinants of log

free CSF :plasma free protease inhibitor trough concentration ratio 35

Table 9: Multivariate analyses using linear regression for determinants of log

free CSF :plasma free protease inhibitor trough concentration ratio 36

Table 10: Final predictive model using linear regression for determinants of

log free CSF:plasma free protease inhibitor trough concentration ratio 37

Figure 3: Association between CSF free protease inhibitor trough

concentration and CSF HIV-1 RNA detection 38

Table 11: Univariate analyses using logistic regression for outcome of

detectable CSF HIV-1 RNA 39

Figure 4: Association between CSF neopterin and CSF free protease inhibitor

trough concentration 40

Table 12: Univariate analysis using linear regression for determinants of CSF

neopterin 41

Table 13: Final predictive model using linear regression for determinants of

CSF neopterin 42

Figure 5: Proportions of participants with CSF free protease inhibitor trough

concentration exceeding IC50 compared between arms 43

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Medicine and Surgery
Palabra Clave	HIV central nervous system protease inhibitors
Committee Chair / Thesis Advisor	Ofotokun, Igho, Emory University Klein, Mitchel, Emory University
Committee Members	Shane, Andi L, Emory University Ziegler, Thomas R, Emory University

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