Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders?

Vassallo, Mattéo; Durant, J.; Biscay, Virginie; Lebrun-Frénay, Christine; Dunais, Brigitte; Laffon, M.; Harvey-Langton, Alexandra; Cottalorda, J.; Ticchioni, Michel; Carsenti, H; Pradier, Christian; Dellamonica, P.

doi:10.1097/qad.0000000000000096

Cited by 58 publications

(33 citation statements)

References 21 publications

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“…Our observations confirm this association, suggesting a significant cut-off of <308 cells/µL for onset of NCI. In contrast, for the CPE score, previous findings do not appear to support ours [39]–[43]. As described above, our results suggest that higher CPE scores may be associated with a higher probability of impairment.…”

Section: Discussioncontrasting

confidence: 99%

Classification Models for Neurocognitive Impairment in HIV Infection Based on Demographic and Clinical Variables

et al. 2014

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ObjectiveWe used demographic and clinical data to design practical classification models for prediction of neurocognitive impairment (NCI) in people with HIV infection.MethodsThe study population comprised 331 HIV-infected patients with available demographic, clinical, and neurocognitive data collected using a comprehensive battery of neuropsychological tests. Classification and regression trees (CART) were developed to obtain detailed and reliable models to predict NCI. Following a practical clinical approach, NCI was considered the main variable for study outcomes, and analyses were performed separately in treatment-naïve and treatment-experienced patients.ResultsThe study sample comprised 52 treatment-naïve and 279 experienced patients. In the first group, the variables identified as better predictors of NCI were CD4 cell count and age (correct classification [CC]: 79.6%, 3 final nodes). In treatment-experienced patients, the variables most closely related to NCI were years of education, nadir CD4 cell count, central nervous system penetration-effectiveness score, age, employment status, and confounding comorbidities (CC: 82.1%, 7 final nodes). In patients with an undetectable viral load and no comorbidities, we obtained a fairly accurate model in which the main variables were nadir CD4 cell count, current CD4 cell count, time on current treatment, and past highest viral load (CC: 88%, 6 final nodes).ConclusionPractical classification models to predict NCI in HIV infection can be obtained using demographic and clinical variables. An approach based on CART analyses may facilitate screening for HIV-associated neurocognitive disorders and complement clinical information about risk and protective factors for NCI in HIV-infected patients.

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Section: Discussioncontrasting

confidence: 99%

Classification Models for Neurocognitive Impairment in HIV Infection Based on Demographic and Clinical Variables

et al. 2014

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“…However, in a French cohort, a prospective neuropsychological analysis indicated that patients receiving treatments with a higher CPE score had a lower risk of clinical deterioration, suggesting that combination ART with better CPE could protect against cognitive deterioration [17].…”

Section: Discussionmentioning

confidence: 99%

Viral and inflammatory markers in cerebrospinal fluid of patients with HIV‐1‐associated neurocognitive impairment during antiretroviral treatment switch

et al. 2015

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ObjectivesThe aim of the study was to evaluate HIV-1 viral load (VL) and inflammatory markers in cerebrospinal fluid (CSF) and neurocognitive performance in patients with neurocognitive impairment (NCI) while they were receiving tenofovir (TDF)/ emtricitabine (FTC)/efavirenz (EFV) and after switching to a regimen with enhanced central nervous system (CNS) penetrability. MethodsThis was a prospective, single-arm pilot study. HIV-1-infected patients with plasma viral suppression and HIV-associated NCI on a regimen including TDF/FTC/EFV were switched to abacavir (ABC)/lamivudine (3TC)/maraviroc (MVC). The Global Deficit Score (GDS) was used to score cognitive function at baseline and 48 weeks after treatment switch. Both CSF and blood samples were taken at baseline and between weeks 24 and 36 after switching. HIV-1 RNA in plasma and CSF was determined by quantitative reverse transcriptase−polymerase chain reaction (qRT-PCR). Inflammatory biomarkers in CSF were measured by enzyme-linked immunosorbent assay (ELISA). ResultsA total of 71 patients receiving TDF/FTC/EFV were screened. Twelve of them (17%) had documented NCI, lacked the human leucocyte antigen (HLA)-B*57:01 haplotype and harboured Chemokine Receptor Type-5 (CCR5)-tropic virus. Eight patients had detectable HIV-1 RNA (between 2.7 and 41.6 HIV-1 RNA copies/mL) in CSF at baseline. All participants had elevated levels of neopterin and Monocyte Chemoattractant Protein 1 (MCP-1) in CSF at baseline. Eight out of 12 patients completed their follow-up assessment after treatment switch. The GDS decreased from 0.55 to 0.4 (P = 0.085). Median HIV-1 RNA in CSF decreased from 3.49 to 2.20 (P = 0.23). Among the inflammation markers in CSF, tumour necrosis factor (TNF)-α decreased significantly from median 0.51 to 0.35 pg/mL (P = 0.027), showing a correlation with the changes in neopterin, interferon (IFN)-γ and interleukin (IL)-6. ConclusionsMost patients with NCI receiving TDF/FTC/EFV had low-level viraemia and/or increased inflammatory markers in CSF. Treatment switching to an MVC-containing regimen with better CNS penetration resulted in a trend towards improvement in neurocognitive status and reduced TNF-α concentrations in CSF.

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“…In studies examining individuals with ART-controlled HIV viremia, HIV DNA in PBMCs correlated with regional brain atrophy highlighting the contribution of peripheral viral reservoirs to CNS pathology [168]. Even the modified HAART regimens that include drugs with better CNS penetration effectiveness (CPE) scores, termed neuro-HAART, have had limited success among patients [169-171]. Researchers have suggested various approaches to targeting latent CNS HIV reservoirs and sources of neuroinflammation such as cytokines, chemokines and oxidative stress that are in play inside the CNS and are refractory to antiretrovirals.…”

Section: Treatment Modalities For Handmentioning

confidence: 99%

Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

2014

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As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

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Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders?

Abstract: Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration.

Cited by 58 publications

References 21 publications

Classification Models for Neurocognitive Impairment in HIV Infection Based on Demographic and Clinical Variables

Classification Models for Neurocognitive Impairment in HIV Infection Based on Demographic and Clinical Variables

Viral and inflammatory markers in cerebrospinal fluid of patients with HIV‐1‐associated neurocognitive impairment during antiretroviral treatment switch

Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

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