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
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
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
|Committee Chair / Thesis Advisor|
|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. ()||2018-08-28||