Human Immunodeficiency Virus‐Associated Dementia: Review of Pathogenesis, Prophylaxis, and Treatment Studies of Zidovudine Therapy

Simpson, David M.

doi:10.1086/520150

Cited by 40 publications

(26 citation statements)

References 75 publications

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“…Only antiretrovirals that penetrate into the CNS in therapeutic concentrations will be able to reduce HIV replication in glial cells and macrophages. This is reflected by the relationship between penetration estimates and either the level of HIV RNA in CSF or neuropsychological performance: the higher the penetration estimates, the lower the HIV RNA levels in CSF (15,16) and the better the neuropsychological performance (5,14,21,23), although not all studies are consistent (16).…”

mentioning

confidence: 99%

Total Raltegravir Concentrations in Cerebrospinal Fluid Exceed the 50-Percent Inhibitory Concentration for Wild-Type HIV-1

Croteau¹,

Letendre²,

Best

et al. 2010

Antimicrob Agents Chemother

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HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC 50 ) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4؉ cell count was 276/l, and 28% of CD4 ؉ cell counts were below 200/l. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r 2 , 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC 50 for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.

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confidence: 99%

Total Raltegravir Concentrations in Cerebrospinal Fluid Exceed the 50-Percent Inhibitory Concentration for Wild-Type HIV-1

Croteau¹,

Letendre²,

Best

et al. 2010

Antimicrob Agents Chemother

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“…Postmortem neuropathology has been observed in a majority of AIDS patients, particularly in children (47). The hallmarks of pathology in HIVE include microglial nodules and multinucleated giant cells in central white matter and deep gray matter, astrogliosis, neuron loss (particularly in hippocampus and basal ganglia), loss of synaptic connections, and myelin pallor (4,16,35).…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Infection of Human Brain-Derived Progenitor Cells

Lawrence

Durham

Schwartz

et al. 2004

J Virol

112

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Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-␣). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-␣ stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5-to 20-fold more infectious virus (27 ng of p24/10 6 cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.

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“…Combination antiretroviral regimens may also reduce viral replication in the central nervous system (CNS). Nucleosides appear to penetrate into the CNS better than protease inhibitors and have been useful in treating patients with human immunodeficiency virus (HIV)-associated dementia (5,12). Many of these agents are substrates for active transporter systems that effectively pump drugs out of the CNS.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

Capparelli

Letendre

Ellis

et al. 2005

Antimicrob Agents Chemother

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The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.Nucleoside reverse transcriptase inhibitors, in combination with potent nonnucleoside reverse transcriptase inhibitors or protease inhibitors, can decrease viral replication, improve immune function, and prolong survival. Combination antiretroviral regimens may also reduce viral replication in the central nervous system (CNS). Nucleosides appear to penetrate into the CNS better than protease inhibitors and have been useful in treating patients with human immunodeficiency virus (HIV)-associated dementia (5, 12). Many of these agents are substrates for active transporter systems that effectively pump drugs out of the CNS. Cerebrospinal fluid (CSF) and plasma exhibit different viral dynamics, indicating that the CNS may serve as an independent reservoir for HIV replication (4, 6). Optimal antiretroviral concentrations in the CNS are necessary to limit local HIV replication and prevent the development of drug-resistant virus and overall treatment failure (11). A few pharmacokinetic evaluations of abacavir in primates and humans have reported limited penetration into the CNS, as characterized by CSF/plasma ratios, ranging from less than 20% to 35% (3, 8). However, most of these evaluations were derived from measurements collected early in the dose interval, which may have biased the estimates of CSF penetration (4, 5, 7). The CSF/plasma concentration ratio is a dynamic measure, and single measurements may not accurately estimate exposure in this potential sanctuary. The ratio of the areas under the CSF and plasma concentration-time curves (AUC CSF / AUC plasma ) is a better estimate of drug exposure, as it accounts for the variability over the entire dosing interval, thus giving a more accurate estimate of CNS penetration (2, 10). Since multiple CSF samples for individual AUC determinations are difficult to collect, we used sparse CSF and plasma concentrations with population pharmacokinetic analysis to estimate the population abacavir AUC CSF /AUC plasma ratio in HIV-infected patients.Plasma and CSF samples were obtained from 54 male adult HIV-infected patients receiving an abacavir-containing regimen. All subjects were consenting participants in prospective research studies conducted at the University of California San Diego HIV Neurobehavioral Research Center and approved by the University of California San Diego Institutional Review Board. Fifty-one subjects (94%) were taking abacavir according to a conventional dosing schedule, (300 mg twice daily), while three received 150 mg, 400 mg, or 600 mg twice daily, respectively. All patients were at steady state and free of opportunistic infection at the time of sample colle...

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Human Immunodeficiency Virus‐Associated Dementia: Review of Pathogenesis, Prophylaxis, and Treatment Studies of Zidovudine Therapy

Abstract: Human immunodeficiency virus (HIV)-

Cited by 40 publications

References 75 publications

Total Raltegravir Concentrations in Cerebrospinal Fluid Exceed the 50-Percent Inhibitory Concentration for Wild-Type HIV-1

Total Raltegravir Concentrations in Cerebrospinal Fluid Exceed the 50-Percent Inhibitory Concentration for Wild-Type HIV-1

Human Immunodeficiency Virus Type 1 Infection of Human Brain-Derived Progenitor Cells

Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

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