Effect of combination antiretroviral therapy on cerebrospinal fluid HIV RNA, HIV resistance, and clinical manifestations of encephalopathy

McCoig, Cynthia; Castrejón, Maria Mercedes; Castaño, Elizabeth; Suman, Onix de; Báez, Carmen; Redondo, Wilfrido; McClernon, Daniel; Danehower, Susan; Lanier, E. Randall; Richardson, Carol; Keller, Amy; Hetherington, Seth; Sáez-Llorens, Xavier; Ramilo, Octavio

doi:10.1067/mpd.2002.125007

Cited by 61 publications

(33 citation statements)

References 30 publications

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“…Capparelli et al (2005) suggested that the cerebrospinal fluid penetration of abacavir might be sufficient to prevent viral replication of the HIV1 virus. This suggestion is contradicted by evidence of the development of different genotypic viral mutations in the brain compared with plasma, indicating discordant viral evolution (McCoig et al, 2002) and lack of viral inhibition in the brain (Kandanearatchi et al, 2004) under abacavir therapy. This is of particular concern in the case of AIDS-dementia complex, which is a continuing problem even with the advent of ART (Smit et al, 2004).…”

Section: Fig 8 a Directional Flux Of [mentioning

confidence: 47%

P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

Shaik¹,

Giri

Pan

et al. 2007

Drug Metab Dispos

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ABSTRACT:P-glycoprotein (P-gp)-mediated efflux at the blood-brain barrier has been implicated in limiting the brain distribution of many anti-HIV1 drugs, primarily protease inhibitors, resulting in suboptimal concentrations in this important sanctuary site. The objective of this study was to characterize the interaction of abacavir with P-gp and determine whether P-gp is an important mechanism in limiting abacavir delivery to the central nervous system (CNS). In vitro and in vivo techniques were employed to characterize this interaction. Abacavir stimulated P-gp ATPase activity at high concentrations. The cellular accumulation of abacavir was significantly decreased by ϳ70% in Madin-Darby canine kidney II (MDCKII)-MDR1 monolayers compared with wild-type cells and was completely restored by the P-gp inhibitors ((R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-␣-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride) (LY335979) and N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918). Directional flux experiments indicated that abacavir had greater permeability in the basolateral-to-apical direction (1.58E-05 cm/s) than in the apical-to-basolateral direction (3.44E-06 cm/s) in MDR1-transfected monolayers. The directionality in net flux was abolished by both LY335979 and GF120918. In vivo brain distribution studies showed that the AUC plasma in mdr1a(؊/؊) CF-1 mutant mice was ϳ2-fold greater than the AUC plasma in the wild type, whereas the AUC brain in the mutant was 20-fold higher than that in the wild type. Therefore, the CNS drug targeting index, defined as the ratio of AUC brain-to-plasma for mutant over wild type, was greater than 10. These data are the first in vitro and in vivo evidence that a nucleoside reverse transcriptase inhibitor is a P-gp substrate. The remarkable increase in abacavir brain distribution in P-gp-deficient mutant mice over wild-type mice suggests that P-gp may play a significant role in restricting the abacavir distribution to the CNS.Abacavir, a carbocyclic nucleoside and a guanosine analog, is a member of the nucleoside reverse transcriptase (NRTI) family of anti-HIV1 agents. Abacavir is metabolized intracellularly to its active form, carbovir triphosphate (Daluge et al., 1997). Abacavir is used in combination with other NRTIs as well as protease inhibitors in active retroviral therapy (ART) (Josephson et al., 2007).HIV1 can infect the CNS at a very early stage of the disease and can lead to the development of AIDS-dementia complex (Ances and Ellis, 2007). The CNS has been cited as a reservoir for the HIV1 virus due to incomplete suppression of the viral replication (Kerza-Kwiatecki and Amini, 1999). Suboptimal concentrations of anti-HIV1 drugs in the CNS can not only lead to incomplete eradication of the virus but also provide ideal conditions for the selection of more virulent mutants (Lipniacki, 2003). Recent reports have highlighted the compartmentalizati...

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Section: Fig 8 a Directional Flux Of [mentioning

confidence: 47%

P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

Shaik¹,

Giri

Pan

et al. 2007

Drug Metab Dispos

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“…HIV-1 associated CNS disease is clinically characterized in children by progressive motor dysfunction, affecting pyramidal and extrapyramidal function as well as fine motor performance [4,11,27,32]. Since the era of HAART, we are seeing less and less of the severe progressive encephalopathy from HIV; however, the pathogenesis and the effect of HAART on the less severe deficits such as psychomotor or neuropsychological dysfunctions are not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…HIV-associated CNS disease in children is manifested by neurological [27] and neuropsychological [45] problems. Varying degrees of intellectual impairment have been documented in symptomatic children with HIV infection [17,18,25,32], while more specific neuropsychological deficits were found in the following domains: language [46], short-term memory [18], visual-spatial functioning [41], executive functioning [2], and fine motor control [3].…”

Section: Introductionmentioning

confidence: 99%

Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease

Koekkoek¹,

Eggermont²,

Sonneville

et al. 2006

J Neurol

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There was no significant difference in psychomotor functioning between children newly treated, previously treated and untreated with HAART over the course of one year. Psychomotor performance deteriorated after 12 months of HAART, which provides important indications concerning the lack of benefits of HAART on psychomotor functions in children despite immunologic reconstitution. Further research with larger sample sizes is needed to confirm these findings.

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“…9 In addition, McCoig et al observed that children infected with HIV who were on combination anti-retroviral therapies showed a significant decline in neurologic abnormalities, as well as viral load (VL), throughout the course of treatment. 10 Nevertheless, the incidence of PHE and the clinical manifestations of PHE have not been systematically assessed since the introduction of HAART. This study was designed to: (1) determine neurologic outcomes in children infected with HIV, including the incidence of PHE and other possible HIV-related outcomes (ADHD, developmental delay); (2) identify the specific risk factors for the development of PHE; (3) identify whether HIV is associated with ADHD and developmental delay in infected children, and; (4) describe the neurologic sequelae of children with arrested PHE in a clinic-based cohort of children with perinatal HIV infection.…”

mentioning

confidence: 99%

Incidence and prevalence of HIV encephalopathy in children with HIV infection receiving highly active anti-retroviral therapy (HAART)

Chiriboga

Fleishman

Champion

et al. 2005

The Journal of Pediatrics

117

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Effect of combination antiretroviral therapy on cerebrospinal fluid HIV RNA, HIV resistance, and clinical manifestations of encephalopathy

Cited by 61 publications

References 30 publications

P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease

Incidence and prevalence of HIV encephalopathy in children with HIV infection receiving highly active anti-retroviral therapy (HAART)

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