Jennifer L. McGuire

Adjuvant therapies for HIV‐associated neurocognitive disorders

HIV‐associated neurocognitive disorder (HAND) is a frequent and heterogeneous complication of HIV, affecting nearly 50% of infected individuals in the combined antiretroviral therapy (cART) era. This is a particularly devastating statistic because the diagnosis of HAND confers an increased risk of HIV‐associated morbidity and mortality in affected patients. While cART is helpful in the treatment of the more severe forms of HAND, there is a therapeutic gap in the milder forms of HAND, where cART is less effective. Multiple adjuvant therapies with various mechanisms of action have been studied (N‐methyl D‐aspartate [NMDA]‐receptor antagonists, MAO‐B inhibitors, tetracycline‐class antibiotics, and others), but none have shown a clear positive effect in HAND. While this lack of efficacy may be because the appropriate therapeutic targets have not yet been determined, we aimed to discuss that study results may also influenced by clinical trial design.

Progressive Multifocal Leukoencephalopathy Associated with Isolated CD8+ T-Lymphocyte Deficiency Mimicking Tumefactive MS

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by lytic infection of oligodendrocytes by the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression. While some case reports have documented PML in individuals with minimal or occult immunosuppression, such cases are very rare and their pathogenesis is not well understood. We report a unique case of a 74 year-old woman who developed PML clinically mimicking tumefactive multiple sclerosis in the context of an idiopathic isolated CD8+ T-lymphocytopenia. Her course subsequently stabilized, concomitant to the development of a cellular immune response directed against JCV. We review the current literature of related cases and discuss the pathogenesis and implications of this rare presentation.

Immune Markers Predictive of Neuropsychiatric Symptoms in HIV-Infected Youth

ABSTRACT The purpose of this study was to evaluate possible associations between systemic immune dysregulation (activated CD8+ T lymphocytes and natural killer [NK] cell count/function) and symptoms of depression and anxiety in youth with horizontally (behaviorally) acquired HIV infection. This secondary analysis of a previously collected prospective cohort included 323 youth with horizontally acquired HIV infection enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) cohort of the NICHD/NIH. A multivariable linear regression model with generalized estimating equations for intraindividual repeated measures was used to examine the relationship between flow cytometry measurements of activated T lymphocytes (CD8+ CD38+), NK cells (CD3− CD16+ CD56+), and NK cell functional activity (lytic units per NK cell and per peripheral blood mononuclear cell) and their association with subsequent symptoms of depression (Center for Epidemiologic Studies depression scale) and anxiety (Revised Childrens Manifest Anxiety Scale). Higher measures of NK cell functional activity were associated with fewer anxiety symptoms measured 12 months later in crude and adjusted analyses. Higher counts of activated T cells were associated with fewer depression symptoms measured 12 months later in adjusted analysis. NK cell function and activated T-lymphocyte count may be related to subsequent symptoms of depression and anxiety.

Modeling and Simulation Approach to Support Dosing and Study Design Requirements for Treating HIV-Related Neuropsychiatric Disease with the NK1-R Antagonist Aprepitant

Psychiatric illness is common in HIV-infected patients and underlines the importance for screening not only for cognitive impairment but also for co-morbid mental disease. The rationale for combining immunomodulatory neurokinin- 1 receptor (NK1-R) antagonists with combined antiretroviral therapy (cART) is based on multimodal pharmacologic mechanisms. The NK1-R antagonist aprepitants potential utility as a drug for depression is complicated by >99.9% protein binding and both enzyme inhibition and induction of CYP3A4. A population-based PK model developed from a pilot Phase 1B trial in 19 HIV-infected patients (125 or 250 mg/d aprepitant for 2 weeks) was modified to account for enzyme induction and impact of an exposure enhancer on CYP3A4 metabolism. Likelihood of clinical success in depression was assessed based on achievement of target trough plasma concentration and evaluated using Monte Carlo simulation. Scenarios were generated for varying daily dose (375, 625, 750 and 875 mg), pharmacokinetic variability, exposure enhancement (EE), duration (2 and 6 months) and sample size (n=12 and 24/arm). Daily dosing of ≥ 625 mg with EE yielded desirable troughs (based on in vitro infectivity experiments) of > 2.65 ug/mL for the majority of virtual patients simulated. Results are dependent on the degree of exposure enhancement and extent of enzyme induction. Actual threshold exposure requirements for aprepitant in HIV-associated depression are unknown though preclinical evidence supports trough levels > 2.65 ug/mL. If 100% NK1r blockage is necessary for efficacy, doses of 875 mg (625 mg with EE) or higher may be required. The benefit of aprepitant on innate immunity(natural killer cells) and absence of negative effects onex vivo neutrophil chemotaxis alleviates concerns regarding drug dependent inhibition (DDI)-mediated infection risk.

PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions?

Receptor occupancy studies are becoming commonplace for verifying drug mechanism of action and selecting early development candidates. Positron emission tomography (PET) has been applied to pharmacodynamic (PD) studies in several therapeutic areas including neurology, cardiology, and oncology. Prospective use of PET to define dosing requirements has been proposed particularly for central nervous system (CNS)-targeted drugs; however, correlations with clinical outcomes have been mostly anecdotal and not causally established.