Minocycline treatment for HIV-associated cognitive impairment Results from a randomized trial

Department of Neurology, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave., 301 Building, Suite 2100, Baltimore, MD 21224, USA.
Neurology (Impact Factor: 8.29). 09/2011; 77(12):1135-42. DOI: 10.1212/WNL.0b013e31822f0412
Source: PubMed


We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment.
HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination.
A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group.
Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment.

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    • "Furthermore, minocycline, chloroquine and simvastatin can inhibit mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs) and P38 kinases (P38Ks)) involved in generating inflammatory responses [20]. In a clinical trial minocycline treatment was found to be unsuccessful in improving the neurocognitive outcome in patients with cognitive impairment [21]. On the contrary, in a simian immunodeficiency virus (SIV) model early administration of minocycline was reported to be effective against striatal dopaminergic system dysfunction, suggesting that timely treatment initiation may have an effect on minocycline efficacy [15]. "
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    ABSTRACT: Background Neuroinflammation is a common immune response associated with brain human immunodeficiency virus-1 (HIV-1) infection. Identifying therapeutic compounds that exhibit better brain permeability and can target signaling pathways involved in inflammation may benefit treatment of HIV-associated neurological complications. The objective of this study was to implement an in vivo model of brain inflammation by intracerebroventricular administration of the HIV-1 viral coat protein gp120 in rats and to examine anti-inflammatory properties of HIV adjuvant therapies such as minocycline, chloroquine and simvastatin. Methods Male Wistar rats were administered a single dose of gp120ADA (500 ng) daily for seven consecutive days, intracerebroventricularly, with or without prior intraperitoneal administration of minocycline, chloroquine or simvastatin. Maraviroc, a CCR5 antagonist, was administered intracerebroventricularly prior to gp120 administration for seven days as control. Real-time qPCR was used to assess gene expression of inflammatory markers in the frontal cortex, hippocampus and striatum. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) secretion in cerebrospinal fluid (CSF) was measured applying ELISA. Protein expression of mitogen-activated protein kinases (MAPKs) (extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs) and P38 kinases (P38Ks)) was detected using immunoblot analysis. Student’s t-test and ANOVA were applied to determine statistical significance. Results In gp120ADA-injected rats, mRNA transcripts of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) were significantly elevated in the frontal cortex, striatum and hippocampus compared to saline or heat-inactivated gp120-injected controls. In CSF, a significant increase in TNF-α and IL-1β was detected. Maraviroc reduced upregulation of these markers suggesting that the interaction of R5-tropic gp120 to CCR5 chemokine receptor is critical for induction of an inflammatory response. Minocycline, chloroquine or simvastatin attenuated upregulation of IL-1β and iNOS transcripts in different brain regions. In CSF, minocycline suppressed TNF-α and IL-1β secretion, whereas chloroquine attenuated IL-1β secretion. In gp120-injected animals, activation of ERK1/2 and JNKs was observed in the hippocampus and ERK1/2 activation was significantly reduced by the anti-inflammatory agents. Conclusions Our data demonstrate that anti-inflammatory compounds can completely or partially reverse gp120-associated brain inflammation through an interaction with MAPK signaling pathways and suggest their potential role in contributing towards the prevention and treatment of HIV-associated neurological complications.
    Journal of Neuroinflammation 05/2014; 11(1):91. DOI:10.1186/1742-2094-11-91 · 5.41 Impact Factor
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    • "In the present study, minocycline treatment was initiated at 21 days p.i., an asymptomatic timepoint occurring after the acute phase of infection but before the establishment of chronic infection and emergence of clinical symptoms. This is in contrast to the recent clinical trials, in which treatment was given to patients already displaying evidence of advanced, chronic infection (indicated by low CD4 counts, time since HIV diagnosis, and/or presence of neurocognitive impairment) [97], [120], [121]. Thus, particular attention should be paid towards whether minocycline can prevent immune pathogenesis as compared to reversing it. "
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    ABSTRACT: HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo.
    PLoS ONE 04/2014; 9(4):e94375. DOI:10.1371/journal.pone.0094375 · 3.23 Impact Factor
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    • "Furthermore, the authors acknowledged limitations in the design of their study (e.g. its small size, short duration and the absence of an untreated control group) that could have led to a type II error and a reduced power to detect effects of minocycline. Nevertheless , the usefulness of minocycline's neuroprotective properties in the treatment of HIV-infection associated cognitive impairment was also ruled out by a clinical trial recently conducted by Sacktor et al. (2011). "
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    British Journal of Pharmacology 02/2013; 169(2). DOI:10.1111/bph.12139 · 4.84 Impact Factor
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