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Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort - pdf attached
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AIDS:
POST AUTHOR CORRECTIONS, 30 November 2010
"Our analyses suggest that careful selection of antiretroviral regimens could increase the CPE by at least one unit for many individuals, and may yield neurocognitive benefits proportionate to the differences seen in neurocognitive impairment between participants with and without an AIDS diagnosis. Improved neurocognitive function would be expected to have an impact on activities of daily living [21], including medication adherence [22,23], driving [24], and employment [25]. To put into context the level of neurocognitive impairment in this group of individuals, it should be noted that we recently found that 26% of 1160 ALLRT participants analyzed had mild-to- moderate impairment at their first visit, and 22% of 991 with at least one follow-up visit had sustained impairment [5]...........however, based on the small, yet statistically significant, magnitude of the effect, it is not completely clear what the extent of these changes would be. Such a strategy should be tested in randomized clinical trials in which groups of HIV-infected individuals with a greater likelihood of neurocognitive impairment (such as those with nadir CD4 cell count <200 cells/ml) might best be able to demonstrate improvement."
Marlene Smurzynskia, Kunling Wua, Scott Letendreb, Kevin Robertsonc, Ronald J. Boscha, David B. Cliffordd, Scott Evansa, Ann C. Colliere, Michael Taylorf and Ronald Ellisg
aHarvard School of Public Health, Department of Biostatistics, Boston, Massachusetts, bUniversity of California, San Diego, Antiviral Research Center, San Diego, California, cUniversity of North Carolina at Chapel Hill, Neurology, Chapel Hill, North Carolina, dWashington University, St Louis, Missouri, eUniversity of Washington and Harborview Medical Center, Seattle, Washington, fUniversity of California, San Diego, Psychiatry and HIV Neurobehavioral Research Center, San Diego, California, and gUniversity of California, San Diego, Neurosciences and HIV Neurobehavioral Research Center, San Diego, California, USA.
Correspondence to Marlene Smurzynski, PhD, Harvard School of Public Health, FXB Building; Room 605, 651 Huntington Avenue, Boston, MA 02115, USA.
Tel: +1 617 432 2823; fax: +1 617 432 2843; e-mail: msmurzyn@sdac.harvard.edu
Abstract
Objective: Differences in antiretroviral distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of antiretroviral therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive participants with plasma HIV-1 RNA (vRNA) suppression.
Design: Participants with at least 6 weeks ongoing antiretroviral drug use and vRNA less than 50 copies/ml (N = 2636; 83% male, median baseline CD4 T cells: 244 cells/[mu]l) had at least one neuroscreen assessment [Trail Making Test, Part A and B; Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol] at 10 413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). Central nervous system penetration effectiveness (CPE) ranks of 0.0 (low), 0.5 (medium), or 1.0 (high) were assigned to antiretrovirals and summed per regimen, per neurovisit.
Methods: Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to antiretroviral regimen. Covariates were retained if P <= 0.1.
Results: A final model demonstrated that better NPZ3 scores were associated with higher CPE among participants taking more than three antiretroviral drugs (+0.07 per one unit increase in CPE score; P = 0.004) but not among participants with three or less antiretroviral drugs in the regimen (+0.01; P = 0.5). Results were adjusted for demographics, injection drug use, hepatitis C virus serostatus, CD4 cell count (current and nadir), baseline vRNA, antiretroviral experience, and years since first antiretroviral drug use.
Conclusion: Use of antiretroviral drugs with better estimated CNS penetration may be associated with better neurocognitive functioning; some people may require more than three antiretroviral drugs to treat HIV in the CNS. Clinically this means antiretroviral regimens could be designed to optimize estimated CNS penetration without sacrificing virologic and immunologic benefits.
Introduction
HIV enters the central nervous system (CNS) within days of initial infection and is present within the CNS throughout the course of disease, frequently leading to HIV-associated neurocognitive disorders (HAND) [1]. Treatment with antiretroviral drugs can result in significant neurocognitive improvement in many indi- viduals with HAND [2]. Nevertheless, improvement with antiretroviral treatment (ART) varies greatly between individuals [3], and several cohort studies have demonstrated that HAND can persist despite virologic suppression and immune recovery on ART [4,5]. One hypothesized explanation for persisting HAND is inadequate treatment of CNS HIV infection due to relatively poor penetration of many antiretrovirals across the blood-brain barrier [6]. With limited CNS penetration, it is possible that subtherapeutic levels of antiretroviral drugs could lead to the development of resistant virus in the nervous system and might not reverse neurologic deficits as well as antiretroviral drugs with better CNS penetration [7,8]. To draw conclusions regarding the significance of drug penetration into the CNS, it is important to examine persons who have plasma HIV-1 RNA (vRNA) viral suppression. In this group there is an opportunity to assess whether antiretroviral regimens that lead to vRNA suppression have differing effects on neurocognitive impairment.
In this analysis, we use data from the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort. Participants from this prospective study provide a unique opportunity to assess estimated CNS penetration and neurocognitive function; the study consists of a large sample of participants randomized to a wide variety of antiretroviral regimens in ACTG clinical trials, who completed neurocognitive assessments at predetermined visits.
Results
Of the 2636 ALLRT participants analyzed, the majority were male (83%), white, non-Hispanic (53%) with a baseline median age of 40 and 14 years of education; only 8% reported past or current injection drug use (Table 2). Nadir CD4+ T-cell counts were lower than the CD4 cell counts at baseline (median: 182 vs. 244 cells/ml). Participants had a median follow-up time of 4.7 years, which was defined as time from parent clinical trial entry (baseline) to last neuroscreen assessment; median number of NPZ3 scores per participants was 4. The relationship between CD4 T-cell count and CPE was examined; there was no correlation between a participant's CD4 cell count and their CPE rank (Spearman correlation coefficient: first neurologic visit, -0.05; second neurologic visit, -0.04).
The overall median CPE rank score was 2.0 (first quartile, third quartile): (1.5, 2.5; 73%,
In univariate regression analyses, there was no association between CPE rank and NPZ3 scores [estimate of the change in NPZ3 score per one unit in CPE score: -0.0049, 95% confidence interval (95% CI -0.0318, 0.0219), P=0.7]. However, there was effect measure modification between the CPE score and the total number of antiretroviral drugs in the regimen. An association was seen in the observations in which there were more than three antiretrovirals in the regimen [estimate: 0.07, 95% CI (0.02, 0.11), P=0.005] but not where there were three antiretrovirals or less in the regimen [estimate: -0.02, 95% CI (-0.05, 0.02), P = 0.3]. Injection drug use [estimate: -0.12, P = 0.03] and a positive hepatitis C virus (HCV) serostatus [estimate: -0.18, P<0.001] were independently associated with worse performance on the neuroscreen assessment, whereas a nadir CD4 cell count above 200 (vs.
In the final multivariate linear regression model, when adjusting for potential confounders in which P500 vs.
The same multivariate model (same covariates) was run using a dichotomous rather than a continuous CPE score to examine the role of particular CPE thresholds on NPZ3 score. The estimate using a CPE threshold of 2.0 (>2.0 vs. < /=2.0) was 0.11 (95% CI 0.04, 0.18; P = 0.002) among participants with more than three antiretroviral drugs in the regimen and 0.02 (95% CI -0.05,0.08; P = 0.6) among participants with three antiretrovirals or less.
Discussion
Among our large study population of HIV-positive individuals on antiretroviral treatment who had vRNA less than 50 copies/ml, those taking regimens with more than three antiretroviral drugs and with better predicted CNS penetration had better neurocognitive outcomes, after adjusting for other potentially confounding factors, although the magnitude of this effect was not large. The same association was not seen among participants taking three antiretrovirals or less. One explanation for these findings is that the better penetrating more than three- drug regimens have more of an effect on neurocognitive functioning than the worse penetrating more than three- drug regimens; this same effect may not be as apparent among participants taking three-drug regimens or less. An additional explanation is that some people may require more than three antiretroviral drugs to reach sufficiently high drug penetration to treat HIV in the nervous system.
To provide a frame of reference for interpreting the magnitude of the CPE effect on neurocognitive outcome we compare it to the magnitude of the effect of nadir CD4 cell count, an important risk factor for HAND [5,19,20]. The impact of a one-unit increase in CPE on neurocognitive outcome among participants taking more than three antiretroviral drugs (estimate: 0.07; P 1/4 0.004) was similar in magnitude to the difference in outcome between participants with a nadir CD4 cell count above 200 vs. 200 cells/ml or less (estimate 0.06; P 1/4 0.08). Our analyses suggest that careful selection of antiretroviral regimens could increase the CPE by at least one unit for many individuals, and may yield neurocognitive benefits proportionate to the differences seen in neurocognitive impairment between participants with and without an AIDS diagnosis. Improved neurocognitive function would be expected to have an impact on activities of daily living [21], including medication adherence [22,23], driving [24], and employment [25]. To put into context the level of neurocognitive impairment in this group of individuals, it should be noted that we recently found that 26% of 1160 ALLRT participants analyzed had mild-to- moderate impairment at their first visit, and 22% of 991 with at least one follow-up visit had sustained impairment [5].
To eliminate potential biases related to differences in antiretroviral regimen potency, indexed by residual plasma viremia, we limited the analysis to participants who had achieved viral suppression on their antiretroviral regimen (vRNA <50 copies/ml). In addition, we were able to use virologic suppression as a proxy for antiretroviral medication adherence; as participants were virally suppressed, we can, with reasonable certainty, state that these participants were consistently taking the medications that they reported as their regimen. In addition, participants in this analysis had similar CD4 cell counts regardless of CPE rank. These findings suggest that for participants experiencing neurologic impairment, a switch to a regimen with higher CNS penetration might assist neurologic recovery while maintaining a similar immunologic and virologic profile.
The present analysis has some other distinct advantages over prior analyses. Although other analyses used a cross- sectional study design [26], this analysis provides estimates both of antiretroviral regimen CPE and neuropsycholo- gic outcome over time, and uses a repeated measures analysis method. Additionally, the number of participants included is much larger than in prior studies [17], which strengthens the robustness and potential generalizability of the results. Another clear benefit in this study was that the CPE was estimated using a ranking scale that has been successfully applied in other analyses among a variety of cohorts, worldwide [15,16,18,27]. Letendre et al. [15,16] have developed an adaptable approach to estimating the CNS penetration of available antiretroviral agents, including nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry inhibitors; the system also permits scoring of combination regimens. As described in Methods, this ranking system uses physico- chemical, pharmacokinetic, and pharmacodynamic data to compare antiretrovirals. Although brain parenchymal extracellular concentrations of drugs have been measured by in-vivo microdialysis in animals [28], this is not feasible in humans. Instead, CSF drug concentrations serve as a surrogate measure of CNS pharmacokinetics. Pharma- codynamic data considered include a drug's ability to suppress viral load in CSF and improve neurocognitive performance [15]. The multidimensional, integrative nature of the system yields relative, rather than absolute, rankings. This flexible system is intended to be refined as new drugs and new pharmacokinetic and pharmacody- namic data become available.
Our analyses have limitations. Although many of our participants contributed data from more than one time point during antiretroviral therapy, the analytical tech- nique we used did not assess improvement or decline in cognitive function over time, but rather the concurrent relationship between CNS penetration scores and cognitive function as measured by NPZ3 scores; we did not analyze changes in NPZ3 scores. Also, our data were limited to evaluations during treatment, and did not include pretreatment neurocognitive assessments that would be needed to evaluate whether the extent of improvement after initiating antiretroviral drugs is related to the regimen's CPE. Although our findings can be discussed in the context of current regimens and their relationship with neurocognitive performance, they cannot be used to assess changes in regimens and how these directly affect changes in neurocognitive status in a particular individual. In terms of generalizability, our cohort was enrolled at multiple sites in the United States and Puerto Rico and is composed primarily of males, whereas the HIV epidemic is expanding in women [29].
Conclusion
These findings suggest that optimizing regimens with higher CPE scores could yield improved neurocognitive function without sacrificing the benefits of ART use. These neurocognitive gains could be expected to provide longer term productivity and functional ability in our patients living with HIV infection; however, based on the small, yet statistically significant, magnitude of the effect, it is not completely clear what the extent of these changes would be. Such a strategy should be tested in randomized clinical trials in which groups of HIV-infected individuals with a greater likelihood of neurocognitive impairment (such as those with nadir CD4 cell count <200 cells/ml) might best be able to demonstrate improvement.
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