Article

Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV

Hawaii Center for AIDS, Department of Medicine, University of Hawaii, Honolulu, HI, USA. .
Antiviral therapy (Impact Factor: 3.14). 09/2012; 17(7). DOI: 10.3851/IMP2411
Source: PubMed

ABSTRACT BACKGROUND: Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. METHODS: Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment. RESULTS: Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (β=0.003, P=0.02), CD4(+) T-cell nadir (β=0.001, P<0.01) and gender (β=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5-433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01). CONCLUSIONS: ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.

1 Follower
 · 
89 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early in the HIV epidemic, the central nervous system (CNS) was recognized as a target of infection and injury in the advanced stages of disease. Though the most severe forms of HIV-associated neurocognitive disorder (HAND) related to severe immunosuppression are rare in the current era of widespread combination antiretroviral therapy (cART), evidence now supports pathological involvement of the CNS throughout the course of infection. Recent work suggests that the stage for HIV neuropathogenesis may be set with initial viral entry into the CNS, followed by initiation of pathogenetic processes including neuroinflammation and neurotoxicity, and establishment of local, compartmentalized HIV replication that may reflect a tissue reservoir for HIV. Key questions still exist as to when HIV establishes local infection in the CNS, which CNS cells are the primary targets of HIV, and what mechanistic processes underlie the injury to neurons that produce clinical symptoms of HAND. Advances in these areas will provide opportunities for improved treatment of patients with established HAND, prevention of neurological disease in those with early stage infection, and understanding of HIV tissue reservoirs that will aid efforts at HIV eradication.
    Current HIV/AIDS Reports 01/2015; 12(1). DOI:10.1007/s11904-014-0255-3
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cross-sectional studies show that around half of individuals infected with HIV-1 have some degree of cognitive impairment despite the use of antiretroviral drugs. However, prevalence estimates vary depending on the population and methods used to assess cognitive impairment. Whether asymptomatic patients would benefit from routine screening for cognitive difficulties is unclear and the appropriate screening method and subsequent management is the subject of debate. In some patients, HIV-1 RNA can be found at higher concentrations in CSF than in blood, which potentially results from the poor distribution of antiretroviral drugs into the CNS. However, the clinical relevance of so-called CSF viral escape is not well understood. The extent to which antiretroviral drug distribution and toxicity in the CNS affect clinical decision making is also debated.
    The Lancet Neurology 11/2014; 13(11):1139–1151. DOI:10.1016/S1474-4422(14)70137-1 · 21.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review To summarize contemporary observations regarding the effects of highly active antiretroviral therapy (HAART) on the brain. Recent findings The effects of HAART on the structure and function of the brain during HIV/AIDS is currently a subject of intense interest because the brain is one of the most drug-impenetrable organs that is infected by HIV-1 and as such represents an important reservoir for replication-competent virus. The effects of HAART on neurocognitive impairment caused by HIV-1 infection remain uncertain with both beneficial and adverse outcomes reported with different HAART regimens. Similarly, the effects of individual HAART regimens on viral quantity in cerebrospinal fluid as a surrogate indicator of brain virus burden are variable. Indeed, the situation is further complicated by the ranking of antiretroviral therapies (ARTs) by their central nervous system penetration-effectiveness score on the basis of ART concentrations in cerebrospinal fluid. Experimental studies have also yielded equivocal findings depending on the model and individual ART. At the same time, a burgeoning body of experimental data has demonstrated neurotoxic effects of several ARTs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Summary HAART selection strategies are currently guided by efficacy, resistance testing, toxicity, potential drug interactions and theoretical brain penetration. As improved strategies are developed to target the viral reservoir within the brain, greater knowledge of the effects of ARTs on neural tissues will be needed to operationalize their use in a rational manner that maximizes antiretroviral efficacy and minimizes the neurotoxic complications.
    Current Opinion in HIV and AIDS 11/2014; 9(6):579-584. DOI:10.1097/COH.0000000000000110 · 4.39 Impact Factor