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Publications (3)10.45 Total impact

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    ABSTRACT: Purpose of the study: To investigate if boosted protease inhibitor monotherapy is associated with a higher risk of neurocognitive impairment (NCI). Methods: HIV-infected patients from two hospitals in Madrid (Spain) without concomitant major neurocognitive confounders, currently receiving for ≥1 year lopinavir/ritonavir (LPV) or darunavir/ritonavir (DRV) as monotherapy or with two N(t)RTIs were included if they had prolonged (≥1 year) plasma viral suppression (<50 c/mL, single blip allowed). Patients underwent full neurocognitive assessment (7 domains) by two psychologists blinded to the treatment group. NCI was defined as per 2007 Frascati criteria using demographically adjusted normative scores. Rates of NCI and the association between NCI and boosted protease inhibitor monotherapy, adjusted by significant confounders, were analyzed. Two categories of monotherapy duration were considered: short-term (1-2 years) and long-term (2-9 years). We evaluated as potential confounding variables: demographics, HIV risk factor, AIDS, CD4 (nadir/current), smoking, alcohol/illicit drug use, prior medical, neurological and psychiatric disease, HCV coinfection, years of ART, prior blips, time with HIV viral suppression, type of protease inhibitor, lipids and HOMA index. Summary of results: 191 patients (89.5% Caucasian) were included (Table 1). Proportion (95% CI) with NCI: Overall: 27.2% (20.9-33.6, all asymptomatic or mild). Triple therapy: 31.6 (22.1-41.0). 1-2 years of monotherapy (n=40): 25.0 (11.3-38.7). 2-9 years of monotherapy (n=56): 21.4 (10.5-32.3) No differences in rates of NCI were found by treatment group (p=0.38). In our regression model confounding variables for NCI were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by those variables the odds ratio (95% CI) for NCI of patients receiving boosted protease inhibitor monotherapy monotherapy during 1-2 years was 0.85 (0.29-2.50) and for 2-9 years was 0.40 (0.14-1.15). Conclusions: Boosted protease inhibitor monotherapy, regardless of duration, was not associated with a higher rate of neurocognitive impairment than triple drug ART. These results call into question the ability of neuropenetrance scores to predict the neuroefficacy of antiretroviral regimens in HIV-infected patients with adequate blood viral suppression.
    Journal of the International AIDS Society 11/2012; 15(6):18179. · 3.94 Impact Factor
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    ABSTRACT: Boosted protease inhibitor (bPI) monotherapy has demonstrated high efficacy for maintaining viral suppression in the blood. bPI monotherapy has the theoretical advantage of avoiding the long-term toxicity associated with the use of nucleoside reverse transcriptase inhibitors. Concern about the efficacy of bPI monotherapy in preventing HIV replication in the CNS is one reason that has precluded the widespread use of this therapeutic strategy. In several studies, a low CNS penetration-effectiveness (CPE) score has been associated with a higher risk of virological failure in the CNS and with neurocognitive impairment. Since the CPE score is substantially lower for bPI monotherapy than for triple-drug highly active antiretroviral therapy (HAART), it has been postulated that bPI monotherapy might have a higher risk for CNS virological failure and neurocognitive impairment. However, the available evidence, although limited, does no support this notion. Lopinavir and darunavir achieve CSF drug levels that are sufficient to fully suppress HIV replication. In clinical trials, when compared with triple-drug HAART, patients receiving bPI monotherapy with lopinavir and darunavir who maintain full virological suppression in plasma do not appear to be at a higher risk of discordant HIV replication in the CSF or of neuropsychiatric adverse events. It should be noted that several studies have suggested that nucleoside reverse transcriptase inhibitors might have neurotoxic effects and, consequently, bPI monotherapy might be able to avoid the CNS toxicity induced by nucleosides. It is clear that more studies including detailed neurocognitive testing are needed to completely establish the risk/benefit ratio of bPI monotherapy or triple-drug HAART for preserving neurocognitive function in HIV-infected patients.
    Journal of Antimicrobial Chemotherapy 06/2011; 66(9):1954-62. · 5.34 Impact Factor
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    ABSTRACT: Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV-1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS.
    Revista de neurologia 01/2011; 52(2):101-11. · 1.18 Impact Factor