Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system

PURPOSE OF REVIEW: The epidemiology of HIV infection is changing rapidly in the era of highly actively antiretroviral therapy, as the use of such therapy is increasing in all countries. This has had a significant impact on the neurological manifestations of HIV infection, posing new challenges in diagnosis and treatment. This review provides a critical analysis of the recent literature on the impact of highly actively antiretroviral therapy on HIV-related neurological complications and changes in treatment strategies. RECENT FINDINGS: It is becoming clear that the brain is an important reservoir for the virus, and neuroinflammatory and neurodegenerative changes may continue despite the adequate use of highly actively antiretroviral therapy. Although this antiretroviral therapy has had a significant impact on the severity of HIV dementia, cognitive impairment persists. With improvement in the immune status following treatment with antiretrovirals, in rare cases the brain can become a target of the immune reconstitution. SUMMARY: Highly actively antiretroviral therapy may need to be optimized in patients with HIV-associated cognitive impairment to achieve maximal central nervous system penetration; however, this therapeutic strategy may not be sufficient for halting the process. In some instances, the antiretroviral drugs themselves may become the problem. New strategies for neuroprotection that also target host genes which control HIV replication are being developed.     

Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy

BACKGROUND: Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA. OBJECTIVE: To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART. DESIGN: Multicenter cohort study. SETTING: Academic neurology departments. PATIENTS: A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/microL or with cognitive symptoms and CD4 cell counts less than 300/microL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor alpha were quantified. RESULTS: The mean +/- SD age was 41.5 +/- 7.2 years, and the mean +/- SD educational level was 12.3 +/- 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean +/- SD CD4 cell count was 136.8 +/- 87.9/microL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log(10) CSF HIV RNA copies per milliliter was 2.6 +/- 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients (P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor alpha correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits. CONCLUSIONS: In contrast to observations in individuals not treated with CART, we found no relationship between CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD.     

Adaptation of antiretroviral therapy in human immunodeficiency virus infection with central nervous system involvement

The authors describe a patient with known human immunodeficiency virus (HIV)-1 infection who presented with two generalized seizures and was found to have extensive white matter disease and a left/bilateral temporo-occipital focal slowing on electroencephalography (EEG). There were no magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) indications for opportunistic infection. Plasma viremia was controlled, whereas viral replication was uncontrolled in CSF. CSF-specific genotype-guided adaptation of the antiretroviral therapy in order to optimize central nervous system (CNS) penetration resulted in clinical improvement and normalization of MRI and EEG. Our case report illustrates the importance of individualized antiretroviral therapy in HIV infected patients with neurological complications.     

Antiepileptic therapy in patients with central nervous system malignancies

More than 200,000 patients are diagnosed with primary or metastatic brain tumors each year in the United States. Of these patients, 20% to 40% will develop seizures at presentation, and another 20% to 40% will require treatment for seizures during their illness. Although the use of antiepileptic drugs (AEDs) in patients who have had seizures seems reasonable, the issue of prophylactic AED use for patients who have not had a seizure is an intensely debated subject. The American Academy of Neurology released a position statement in May 2000 addressing the use of anticonvulsants in newly diagnosed brain tumor patients who have never had a seizure. After a review of the literature, including all trials showing class I evidence, multivariate analysis using calculated odds ratios failed to show a prophylactic benefit of preventing a first seizure versus the risk of side effects and recommended not using prophylactic anticonvulsants in newly diagnosed patients with brain tumor. Despite this recommendation, a recent survey of the American Association of Neurologic Surgeons revealed that most neurosurgeons still use anticonvulsants prophylactically in patients with brain tumor. This review mainly includes primary brain tumors, but most of the concepts are transferable to patients with metastatic tumors.     

HIV‐associated central nervous system diseases in the recent combination antiretroviral therapy era

Background and purpose: Data describing the incidence and survival of HIV‐related central nervous system diseases (CNS‐D) in recent years are sparse. Methods: Between 1996 and 2007, adult subjects without previous CNS‐D within a large UK cohort were included (n = 30 954). CNS‐D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS‐D were evaluated using Poisson regression analysis and Kaplan–Meier techniques. Results: Six hundred and thirteen new CNS‐D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS‐D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P = 0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100 000 copies/ml were independently associated with the development of CNS‐D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival. Conclusions: An ongoing decline in the incidence of CNS‐D has been observed in very recent years. Mortality following such a diagnosis remains high.     

Biomarkers of HIV related central nervous system disease

In this review we critically assess biomarkers of the direct effects of HIV related brain disease. This area is becoming increasingly complex because of the presence of confounds and varying degrees of activity of HIV brain disease. Sensitive and specific biomarkers are urgently needed although existing biomarkers do have some utility. The review will focus on the practical implications of the more established biomarkers. We discuss blood, cerebrospinal fluid and neurophysiological biomarkers but not neuroimaging techniques as they are beyond the scope of this review.     

Biomarkers of HIV related central nervous system disease

In this review we critically assess biomarkers of the direct effects of HIV related brain disease. This area is becoming increasingly complex because of the presence of confounds and varying degrees of activity of HIV brain disease. Sensitive and specific biomarkers are urgently needed although existing biomarkers do have some utility. The review will focus on the practical implications of the more established biomarkers. We discuss blood, cerebrospinal fluid and neurophysiological biomarkers but not neuroimaging techniques as they are beyond the scope of this review.     

Electrophysiological indices of central and peripheral nervous system function during theophylline therapy

Electrophysiological parameters including the EEG, somatosensory evoked potentials (SEP), F waves, long loop reflexes and peripheral nerve conduction velocities were assessed during the 15th week of theophylline therapy, with serum levels maintained in the low therapeutic range, in young, healthy male volunteers (n = 7). Recordings were repeated 1 week after vitamin B6 supplementation and finally 6-7 weeks after the cessation of medication. Alpha amplitudes were significantly lower during theophylline therapy compared to the posttreatment baseline recording. The SEP findings failed to reveal any significant differences between the three recordings, as was the case with peripheral nerve conduction velocities and long loop reflexes. The average F wave latencies during theophylline therapy were significantly shorter, and the percentage F waves recorded was higher, compared to the baseline recordings. These findings suggest that relatively long-term theophylline therapy has stimulatory effects on aspects of electrical activity in the brain and spinal cord. These effects appeared to be unchanged after vitamin B6 supplementation for 1 week.     

Magnetic field influence on central nervous system function

The effects of strong static magnetic fields on the excitability of striate cortex in adult cats was studied. The visual evoked response was used as a measure of cortical excitability. In all animals a 1200-G field was associated with a significant decrease in both amplitude and variability of the evoked response. This effect began more than 50 s after the field was turned on and persisted, even after the field was turned off, for several minutes. This phenomenon appears to be due to action of the magnetic field at the synapse rather than on axonal conduction.     

Immune problems in central nervous system cell therapy

Transplantation of cells and tissues to the mammalian brain and CNS has revived the interest in the immunological status of brain and its response to grafted tissue. The previously held view that the brain was an absolute “immunologically privileged site” allowing indefinite survival without rejection of grafts of cells has proven to be wrong. Thus, the brain should be regarded as a site where immune responses can occur, albeit in a modified form, and under certain circumstances these are as vigorous as those seen in other peripheral sites. Clinical cell transplant trials have now been performed in Parkinson’s disease, Huntington’s disease, demyelinating diseases, retinal disorders, stroke, epilepsy, and even deafness, and normally are designed as cell replacement strategies, although implantation of genetically modified cells for supplementation of growth factors has also been tried. In addition, some disorders of the CNS for which cell therapies are being considered have an immunological basis, such as multiple sclerosis, which further complicates the situation. Embryonic neural tissue allografted into the CNS of animals and patients with neurodegenerative conditions survives, makes and receives synapses, and ameliorates behavioral deficits. The use of aborted human tissue is logistically and ethically complicated, which has lead to the search for alternative sources of cells, including xenogeneic tissue, genetically modified cells, and stem cells, all of which can and will induce some level of immune reaction. We review some of the immunological factors involved in transplantation of cells to CNS.     

Use of gene therapy in central nervous system repair

Recent advances have increased our molecular understanding of the central nervous system (CNS), in both health and disease. In order to realize the clinical benefits of these findings, new molecular-based therapies need to be developed, such as CNS gene therapy. Although the field has suffered setbacks, it remains an attractive technology for providing new therapies in the post-genomic world. The development of new vectors, and their extensive application in animal models of CNS disease, provides evidence suggesting that gene therapy will eventually become an accepted clinical option. In fact, the first gene therapy clinical trial for Parkinson's disease has recently begun. This review discusses how gene therapy has been applied in animal models, and how it may be used to repair the damage caused by CNS diseases and trauma in human beings. Furthermore, it explores how such treatments may be combined with, and augment, more conventional therapeutic approaches.     

Regulation and function of central nervous system chemokines

In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokines, in CNS inflammatory pathology. Chemokines are a family of proinflammatory cytokines which are able to stimulate target-cell-specific directional migration of leukocytes. Because of this feature, chemokines may be potent mediators of inflammatory processes. We have previously reported observations indicating that chemokines may be involved in the process of lesion formation during autoimmune inflammation within CNS, and, in particular, are likely participants in the process of influx of inflammatory cells into the CNS parenchyma. We observed also that mechanical injury of brain and subsequent post-traumatic inflammation may in part be mediated by chemokines. Chemokines undoubtedly co-operate with cell-associated adhesion molecules during recruitment of leukocytes from blood to CNS. The sequential expression of soluble and membrane-bound signals for leukocyte migration is an intricate process that can be interrupted by a variety of strategies. Our data suggest that chemokines may represent a promising target for future therapy of inflammatory conditions, including CNS inflammation resulting from varied insults.     

Multi-modality therapy leads to longer survival in primary central nervous system lymphoma patients

BACKGROUND: Primary central nervous system lymphoma (PCL) is more frequently encountered by neurosurgeons given the increasing incidence among both nonimmunocompromised and immunocompromised patients. The most frequent surgery is stereotactic biopsy. Historically, radiation therapy has been the standard treatment modality for this disease and median survival was in the 15-month range. More recently, multi-modality therapy combining radiation therapy with chemotherapy (systemic, intrathecal, and/or intra-arterial) have resulted in longer survivals. We reviewed survival data for our series of patients treated for PCL over the last decade. METHODS: Thirty-four patients with histologically confirmed PCL were treated at our center. Multivariate Cox regression analysis was performed to determine which factor(s) (age, gender, HIV status, Karnofsky Performance Scale, chemotherapy, single modality therapy, histology, location, number of lesions, surgical resection) had a significant impact on survival. RESULTS: The overall median survival was 19 months. Patients receiving multi-modality therapy (n=17) (chemotherapy and radiation) had a median survival of 34 months compared to four months for patients receiving single modality therapy (n=17 including seven HIV positive patients). Multi-modality therapy was the only significant factor affecting survival in this multivariate analysis (p<0.0001). CONCLUSIONS: Chemotherapy plus radiotherapy significantly enhances survival over patients treated with single modality therapy alone. Quality of life issues should be addressed on a case by case basis as additional treatment modalities are initiated.     

The effect of highly active antiretroviral therapy on outcome of central nervous system herpesviruses infection in Cuban human immunodeficiency virus-infected individuals

With the rapid progress in the development of highly active antiretroviral therapy (HAART), the observed patterns in human immunodeficiency virus (HIV) encephalitis has changed, allowing herpesvirus (HV) infection to be controlled. HAART was first administered to HIV patients in Cuba in 2001. Consequently with the aim of investigate the behavior of the HVs causing neurological disorders in this population in the post-HAART era, the authors perform a clinical evaluation by a multiplex nested polymerase chain reaction (PCR) assay for simultaneous detection of human HVs--herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV). The authors studied 241 samples of cerebrospinal fluid (CSF) received at the Sexually Transmitted Diseases Laboratory between 2001 and 2005 inclusive. Of the 241 CSF studied, 10.4% resulted positive for HV infections. Of these, 92% of patients were acquired immunodeficiency syndrome (AIDS) individuals at the C3 stage. CMV (44%), EBV (28%), and dual-HV (16%) infections were the most important agents identified. The principal clinical manifestations were fever, headache, vomiting, and focal abnormalities; the latter being associated with an increased risk of death. A statistically significant result was observed when central nervous system (CNS) disease evolution was compared between patients who were under HAART against those who were not, before they developed encephalitis. It was therefore concluded that it is more likely that HIV individuals receiving HAART have a better recovery of CNS infections than those who are not receiving it.     

Abnormal contingent negative variation in HIV patients receiving antiretroviral therapy

The contingent negative variation, an event-related potential related to neural activity in the frontal lobe and basal ganglia, neuropsychological tests and structural MRI were used to examine CNS function and structure in HIV-positive patients receiving antiretroviral therapy. Relative to controls, HIV patients had smaller thalamic volume and reduced late contingent negative variation amplitude that correlated with caudal atrophy. Behaviorally, viremic patients were more impaired than virally suppressed patients and controls on neuropsychological measures of psychomotor speed, selective attention and mental flexibility. These results suggest that antiretroviral therapy may not be effective in protecting cortical and subcortical structures against HIV-related neuropathology, regardless of immune function. However, the benefits of antiretroviral therapy on immune function appear to facilitate neurocognitive performance.