Pharmacologic interventions for HIV-associated neurocognitive disorders
HIV-associated neurocognitive disorders (HAND) represent a spectrum of cognitive disorders caused by HIV. HAND typically affects attention, information processing speed, learning and recall memory among other cognitive functions (Antinori 2007). Asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), the milder forms of HAND continue to affect nearly half of HIV-infected individuals nowadays while the more severe form of HAND, HIV-associated dementia (HAD), has become very uncommon since the introduction of highly active antiretroviral therapy (HAART) in 1996 (Figure 1) which consists in the combination antiretrovirals with different mechanisms of action (McArthur 2010, Heaton 2010). The high prevalence of the milder forms of HAND is not insignificant, as those disorders interfere with daily functioning including instrumental activities of daily living (e.g., finance management, housekeeping tasks) even in HIV-infected individuals with ANI, who are by definition asymptomatic but may have interference with activities of daily living when carefully questioned and specifically assessed by task performance-based evaluation. HAND has also implications for adherence to antiretrovirals as it affects prospective memory (i.e., the ability to execute a future intention) (Blackstone 2012).
Figure 1. Prevalence of HAND subtypes by HIV treatment era. Pre-HAART (before 1996) and HAART (after 1996). Adapted from McArthur et al., Ann Neurol 67, 699-714, 2010.
Although the exact way in which HIV causes HAND is unknown, potential mechanisms include HIV replication in the central nervous system (CNS), particularly in the deep regions of the brain called the basal ganglia and the adjacent subcortical white matter, where the most productive HIV infection is typically observed (Boska 2004, Aylward 1995). The specific regional topography mentioned above may explain the neuropsychological impairment pattern observed in HAND. Since neurons have the lowest susceptibility to HIV infection among all cells of the CNS, their dysfunction likely results from infection of neighboring cells such as macrophages and microglia, which are cells with immune functions in the brain. Infection of those cells results in production of viral proteins that have the ability to damage the synapse where communication between neurons occurs. In addition, the same viral proteins have the ability to activate uninfected macrophages, microglial cells and astrocytes (a key cell supporting neurons) which will result in the production of a variety of inflammatory molecules and neurotoxins, leading to further damage to neurons (Figure 2) (Kaul 2001). Some of that additional damage may occur through overstimulation or overactivation of neuron receptors called NMDA receptors, which normally function as part of an excitatory messenger system. However, overactivation of NMDA receptors by those inflammatory molecules and neurotoxins results in accumulation of calcium in the neurons triggering a variety of harmful enzymes and free radicals formation resulting in oxidative stress damage. Other factors such as the use of methamphetamine and co-infection with hepatitis C may enhance damages caused by HIV, particularly through further activation of uninfected macrophages and microglial cells.
Figure 2. Model of HIV-related brain damage. Infected macrophages or microglia release viral proteins (e.g., gp120), cytokines (e.g., TNF-alpha) and chemokines, which in turn activate uninfected macrophages and microglia. Immune activated- and HIV-infected brain macrophages/microglia release potentially neurotoxic substances which induce neuronal injury, synapse damage, and cell death. Neuronal injury is mediated in part by overactivation of NMDA receptor-coupled ion channels that allow excessive influx of Ca2+. This in turn triggers a variety of potentially harmful enzymes, free-radical formation and release of glutamate. Glutamate subsequently overstimulates NMDA receptors on neighboring neurons, initiating further injury. From Kaul et al. Nature, 410, 988-994, 2001.
The very first therapy developed for HAND was the combination of antiretroviral agents to stop HIV replication, and this strategy had robust benefits for cognitive function in HIV-infected individuals, as shown by the marked reduction in the prevalence of its most severe form, HAD (McArthur 2010). However, there is considerable variability in the extent of response to combination antiretroviral agents between individuals. Because of the persistence of HAND in many individuals despite the use of antiretroviral agents, other therapeutic strategies have been investigated. Because of the inferred mechanisms through which HIV causes HAND, predominantly neuroprotective strategies have been evaluated. Memantine is a first generation NMDA receptor antagonist or blocker that is FDA-approved for moderate to severe Alzheimer’s disease. It has been studied in a placebo-controlled study in individuals with HAND, where it was not associated with neurocognitive improvement (Schifitto 2007, Zhao 2010). Selegiline is a monoamine oxidase B inhibitor with anti-oxidant properties and has not shown significant benefit in another placebo-controlled study (Schifitto 2007, Evans 2007). Likewise, other potent investigational antioxidants including CPI-1189 is OPC-14117 have not shown benefit in placebo-controlled studies (Clifford 2002, Dana Consortium 1997). Despite those negative studies, more promising and better-tolerated neuroprotective strategies are being developed. Among these is a second-generation NMDA receptor antagonist or blocker called nitromemantine that selectively blocks overactive NMDA receptors without disrupting normal activity, which may lead to better tolerability and allow the use of higher and more effective doses (Lipton 2007). A combination of erythropoietin and insulin growth factor 1, two FDA-approved biological agents for other indications, is also being investigated, as it has shown remarkable neuroprotection against viral proteins, as well as molecules resulting in excessive activation of NMDA receptors (Kang 2010).
HMG-CoA reductase inhibitors, also called statins (e.g., atorvastatin, simvastatin), which are typically used to treat elevated cholesterol and/or triglycerides, have become of interest because of in vitro evidence of modulation of the immune system, of cell activation, and possibly of HIV replication. In two small studies of HIV+ individuals, there was no appreciable effect of atorvastatin on levels of HIV RNA (a marker of HIV replication) or markers of immune and cellular activation in cerebrospinal fluid (CSF — the fluid surrounding the brain and spinal cord and a surrogate sample for brain tissue) (Probasco 2008, Ganesan 2011). A larger cross-sectional study looking at several statins also failed to show an effect on CSF HIV RNA or neurocognitive performance (Letendre 2007).
Because serotonin (5-hydroxytryptamine) and its receptors may play a role in HIV replication and entry into the cell leading to infection progression, and because depressive mood disorder is a frequent comorbidity in HIV-infected individuals, there has been a growing interest in selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram, sertraline, trazodone) as HIV infectivity modulators. While controlled studies have yet to be conducted, a cross-sectional study has shown that HIV+ individuals on those medications were more likely to have undetectable CSF HIV RNA and to have better neurocognitive performance (Letendre 2007).
Adjunctive strategies with the aim of improving symptoms (without affecting the disease process or mechanism) have very limited or no supportive data for use in HAND. Some of those include psychostimulants such as amphetamine derivatives (e.g., Adderall) and central cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine) which are FDA-approved for mild to severe Alzheimer’s Disease.
Many effective antiretrovirals have been developed to suppress HIV replication throughout the body since the beginning of the AIDS epidemic in the United States. Since 1996, antiretrovirals are typically used in combination of three or more drugs. One potential factor limiting the efficacy of antiretrovirals in the CNS is the blood-CNS barrier, a barrier at the level of the small blood vessels (capillaries) in the brain preventing many molecules from entering the CNS in order to preserve the homeostasis (physicochemical stability) of this critical environment. Only antiretrovirals that penetrate the CNS in therapeutic concentrations will be able to reduce HIV replication in that compartment. Antiretrovirals that achieve higher concentrations in the CNS are associated with a greater likelihood of reduction of HIV RNA levels in CSF (Letendre 2008, Marra 2009), and perhaps better neurocognitive performance (Cysique 2009, Letendre 2004, Tozzi 2009). The determination of how well antiretrovirals penetrate the CNS is complex and based on several factors including, physicochemical characteristics of the drug, measurement of the antiretroviral in the CSF, and effect on HIV RNA levels in the CSF. Further adding to the complexity is the presence of transporters at the blood-CNS barrier that actively pump out drugs, including many antiretrovirals currently in use. Based on those principles, another management strategy of HAND includes the use of antiretrovirals with better CNS penetration.
This approach is currently being evaluated in a multi-site clinical study called Clinical Intervention Trial 2 (CIT2) where HIV+ individuals with HAND are randomized to antiretroviral regimens having different CNS penetration. Some HIV care providers are using the approach in CIT2 in their practice following the algorithm in Figure 3, although the benefits of such approach remain to be demonstrated in the ongoing CIT2 study. A complexity that is being investigated is the possibility that some antiretrovirals may result in adverse effects on brain tissue (Cysique 2009, Robertson 2010, Ciccarelli 2010). Therefore, it needs to be considered whether the benefits of better HIV suppression through greater penetration of antiretrovirals into the CNS may be offset by neurotoxicity. Large U.S. multi-site studies such as CIT2 and the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) hope to shed some light on this question.
Figure 3. Antiretroviral optimization algorithm for HIV-infected individuals with HAND. Adapted from McArthur et al., Ann Neurol 67, 699-714, 2010.
In summary, HAND is still an important problem in HIV-infected individuals despite the use of combination antiretroviral therapy that often achieves HIV suppression of replication to levels below the limit of detection of currently used assays. Although no effective pharmacologic treatments are currently available beyond optimal suppression of HIV replication in the CNS, promising strategies are currently under investigation.
About the author
David Croteau, MD, received his MD degree from Laval University in Quebec City, Canada, and completed his neurology residency training at McGill University in Montreal, Canada. He subsequently completed a clinical fellowship in neuro-oncology at Henry Ford Hospital in Detroit, Michigan. Dr. Croteau then went on to complete a research fellowship with focus on intracerebral drug delivery at the Surgical Neurology Branch of the National Institute of Neurological Disorders and Stroke, national Institutes of Health in Bethesda, Md. In 2009, Dr. Croteau joined the University of California, San Diego (UCSD) as a senior clinical fellow training at the HIV Neurobehavioral Research Center (HNRC) in HIV Neurology/NeuroAIDS and is currently an assistant adjunct professor of neurosciences at UCSD. Dr. Croteau is board certified in neurology both by the Royal College of Physicians of Canada and by the American Board of Psychiatry and Neurology. Dr. Croteau’s research emphasizes his interest in central nervous system pharmacology, blood-CNS barrier, and brain imaging as they relate to HIV infection or complications.
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