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Neurologic Complications

Neurologic Complications

The diagnosis of HIV dementia has become a challenge following the advent of highly active antiretroviral therapy because the clinical spectrum of HIV dementia has changed. Although HIV dementia continues to occur when patients present with immunosuppression, post-HAART era studies show that it may be more likely to occur in HIV-infected persons with higher CD4+ cell counts.1-3 The incidence of HIV dementia has decreased in patients using effective antiretroviral therapy,1,3 but the prevalence of HIV dementia has increased because patients are living longer.4-6
Longitudinal cohort studies of the clinical manifestations of HIV dementia in patients who have received effective antiretroviral therapy have observed changes in the clinical presentation of HIV dementia to a milder form with a variable progression.4,6,7 Therefore, diagnosis of HIV dementia in the HAART era becomes a challenge because we must consider the wide spectrum of its clinical manifestations, from the milder subclinical stages to the more severe deficits. In these patients, the term “dementia” may no longer be appropriate, and the term “minor cognitive-motor disorder (MCMD)” is being used.
Because patients with HIV infection are living longer, comorbid factors, such as aging, drug abuse, and coinfections with hepatitis C virus (HCV), may have an impact on the diagnosis of HIV dementia, the course of the disease, and its treatment. Through proper treatment, HIV infection has become a chronic infection8; therefore, HIV dementia should be considered in the diagnosis and treatment of neurologic complications of HIV infection.
DEFINITION AND DIAGNOSIS
HIV dementia is characterized by a disabling cognitive, behavioral, and motor dysfunction.9 It appears that dementia is rare during the asymptomatic phase of HIV infection,10 even among drug abusers.11,12 In the later stages of HIV infection, however, progression of neurocognitive deficits to frank dementia is more common. In the pre-HAART era, HIV-associated MCMD developed in 17% and HIV dementia in 9% of patients with normal neurocognitive test results and a CD4+ cell count below 200/µL during a 1-year follow-up period.13
Although the incidence of HIV dementia has decreased markedly since the start of the HAART era by 15% to 50%, it continues to be a significant cause of morbidity in infected patients.14 Prevalence, on the other hand, has increased as a result of the widespread use of antiretroviral therapy and the increased survival of HIV-infected patients.6,15 The clinical manifestations of HIV dementia have changed in the post-HAART era, with HIV dementia presenting in a milder form with mixed cognitive phenotypes (subcortical and cortical features), higher CD4+ cell counts, and variable progression patterns.4,6 Recent studies comparing HIV dementia before and after antiretroviral treatment1,2 have found a higher range of CD4+ cell counts (greater than 200/µL) in new cases of HIV dementia.3,4
As mentioned above, the increased survival rate of patients who are receiving effective antiretroviral therapy brings other comorbid factors into consideration in the diagnosis of HIV dementia, such as aging, long-term antiretroviral treatment effects, additive effects of drug abuse, and coinfection with HCV.
Other factors to be considered in the differential diagnosis of a patient with HIV infection and neurocognitive complications include:
nAnxiety.
nDepression.
nAlcohol consumption.
nRecreational drug use.
nMedication side effects.
nMetabolic encephalopathy.
nHypothyroidism.
nVitamin B12 deficiency.
nDrug interactions with protease
inhibitors.
Many terms have been used to define HIV dementia. The terms AIDS dementia complex, HIV dementia, HIV encephalopathy, and HIV-associated dementia complex are synonymous. The term HIV encephalitis (HIVE) should be reserved for the pathologic features of multinucleated giant cell encephalitis with HIV identified in the brain; it should not be used to describe the clinical syndrome.16 HIV dementia was initially defined as AIDS dementia complex (ADC) by Navia and colleagues,17 in order to encompass the constellation of cognitive, motor, and behavioral symptoms that presented in patients with AIDS.18 To establish epidemiologic terminology for the clinical staging of ADC, the Memorial Sloan-Kettering (MSK) scale was proposed by Price and Brew in 1988.18 This scale is used to stage cognitive impairment based on functional disability and motor dysfunction.
Because not all patients with HIV infection present with all the components of ADC, the American Academy of Neurology (AAN) formed an AIDS Task Force to develop a consensus on nomenclature and case definitions for research purposes. From this consensus, it was recognized that HIV-associated cognitive-motor complex presents with a broad spectrum of clinical manifestations and severity. The AAN AIDS Task Force developed criteria for clinical diagnosis in which it identifies 2 categories: a more severe form termed “HIV-associated dementia complex” (HIV dementia) and a milder form termed “HIV-associated MCMD.”19 However, during the course of a patient’s illness, the severity of neurocognitive changes may vary and he or she may move from one category to the other (Figures 1 and 2). HIV-
associated myelopathy was given a separate diagnosis category using AAN criteria.
AAN criteria are based on the demonstration of neurologic, functional, and behavioral disturbances. Following an algorithm of clinical manifestations, patients’ conditions are classified into normal, MCMD, or HIV dementia categories. Several types of evaluations are used to determine the clinical findings; the most common are macroneurologic examination, quality of life questionnaires, depression screening scales (Beck Depression Index and Center for Epidemiologic Studies Depression Scale), Karnofsky score, and Instrumental Activities of Daily Living Scale (IADL).20
The HIV Dementia Scale (HDS) is a rapid screening for HIV dementia that consists of 4 subtests: timed written alphabet, recall of 4 items at 5 minutes, cube copy time, and antisaccadic errors.21 This scale detected HIV dementia in a rapid and reliable way. In an effort to internationalize the HDS so that it could be used cross-culturally, Sacktor and colleagues22 developed the International HIV Dementia Scale (IHDS). The IHDS consists of 3 subtests: finger tapping, timed alternating hand sequence, and recall of 4 items at 2 minutes. It is a sensitive and rapid screening test that is not dependent on language, and although it is not meant to be used to assign a clinical diagnosis, it is useful in identifying patients who need to be referred for a full evaluation.
Other groups, such as the HIV Neurobehavioral Research Center (HNRC), rely mostly on neuropsychological test performance for the diagnosis of HIV dementia. Using different neuropsychological tests, the HNRC group is able to distinguish 3 types of patients with HIV cognitive impairment: those with HIV dementia, those with a milder form of cognitive impairment with decreased performance of activities of daily living (ADL), and those with an asymptomatic dysfunction where there is abnormal neuropsychological test performance without dysfunction of ADL. This classification helps to identify milder forms of HIV cognitive impairment and to follow neuropsychological changes over time in terms of progression and treatment efficacy.23 This test battery is best suited for English-speaking populations with a high level of education.
In view of the increased survival rate of HIV-infected patients, there is a need to determine the prevalence of the neurologic complications of HIV in patients who are receiving antiretroviral therapy. The Neurological AIDS Research Consortium and the AIDS Clinical Trials Group study teams performed a clinical validation of the NeuroScreen diagnostic system.24 This screening test includes the Brief NeuroCognitive Screen, which assesses speed of information processing, mental flexibility, and working memory. Although the test has some limitations, the investigators concluded that the NeuroScreen will be useful for tracking trends in the prevalence of HIV-associated neurologic diseases in large cohorts using combination antiretroviral agents but is less useful for evaluating individual patients.
The pathologic findings in patients with HIV dementia are described as HIVE, which is characterized by multinucleated giant cell
encephalitis, microglial nodules, neuronal loss, alterations in dendritic arbor, and decreased synaptic density.16 Efforts to correlate neurocognitive dysfunction with pathologic findings show a correlation of antemortem cognitive function with postmortem evidence of HIVE.
In the pre-HAART era, a positive predictive value of 95% was observed in patients with HIV dementia or neurocognitive dysfunction who were found at postmortem to have HIVE.25 With the introduction of effective 3-drug regimens, HIV infection has become a chronic infection that not only affects the clinical manifestations of HIV dementia but also its neuropathologic findings.26 Four different forms have been described: (1) an aggressive form with severe HIVE and white matter injury, (2) a form with extensive perivascular lymphocytic infiltration, (3) a “burnout” form of HIVE, and (4) an aging-associated form with amyloid accumulation. These new neuropathologic findings may correlate with the different clinical manifestations of HIV dementia in the HAART era.
Although these scales have been used for the screening, staging, and diagnosis of HIV dementia, there are problems in using them. First, these scales do not measure the subtle cognitive dysfunctions that are more prominent in the post-HAART era. HIV dementia in the post-HAART era is milder, presenting with mixed phenotypes (subcortical and cortical features), a higher CD4+ cell count, and variable progression patterns.4,27,28 These milder forms may only involve neuropsychological testing without interfering with ADL, as shown by the HNRC group. The AAN criteria, ADC terminology, and the MSK scale do not recognize this group of patients. Therefore, there is a need to redefine milder forms of HIV cognitive impairment. Second, with the exception of the HDS and initially the MSK scale, the scales rely heavily on the neuropsychological test performance and may not be appropriate for use in cross-cultural populations. Third, the AAN criteria in particular are not well designed to measure progression of HIV dementia. Therefore, there is a need to have normative values of select neuropsychological tests that can be used cross-culturally and that are not dependent on language fluency or level of education.
Course of HIV Dementia
In the era of HAART, the course of HIV dementia appears to have changed. As a result, distinct subtypes have been proposed recently and include the following (Figure 2):
nSubacute progressive dementia, usually seen in untreated patients with a clinical syndrome of severe, progressive dementia similar to that seen in the pre-HAART era. usuall
nChronic active dementia, often occurs in patients on effective antiretroviral therapy with poor adherence or with viral resistance who are at risk for neurologic progression.
nChronic inactive dementia, often found in patients receiving effective antiretroviral therapy with good drug adherence and effective virologic suppression who have had some recovery from neuronal injury and remain neurologically stable.
nReversible dementia, also found in patients receiving effective antiretroviral therapy with good drug adherence and effective virologic suppression.
These terms are based on the clinical course of the illness and can only be used to classify patients over time. Yet it is critically important to identify patients who are at risk for the development of either the subacute progressive or the chronic active form of HIV dementia. A major effort is currently under way in several laboratories, including our own, to use mass spectroscopic techniques in the cerebrospinal fluid (CSF) to identify such patients, so that aggressive intervention may be taken to halt the progression of the manifestations.
Diagnostic Studies
Cerebrospinal fluid. CSF may need to be sampled in the diagnosis of HIV dementia to exclude opportunistic processes such as cryptococcal or tuberculous meningitis, but to date, no definitive or diagnostic CSF profile for HIV dementia has entered clinical practice. Elevated levels of HIV RNA and immune activation markers occur in patients with HIV dementia who are treatment-naive.
HIV RNA level. CSF levels of HIV RNA correlate with the severity of neurologic deficits in untreated persons,29,30 but levels of CSF HIV RNA or immune activation markers are attenuated in treated persons and do not correlate well with neurologic status.6 Decline in CSF HIV RNA levels with effective antiretroviral therapy correlates with the successful reversal of neurologic deficits.31
Immune activation markers. Various CSF markers of immune activation or neuronal injury also correlate with dementia severity but have not been validated in treated patients. Before the use of effective antiretroviral therapy, the immune activation marker beta2-microglobulin was useful in diagnosis, particularly in mild dementia in the absence of opportunistic infections, and a value greater than 3.8 mg/dL had a positive predictive value of 88%.32-34 Quinolinic acid levels are also increased in patients with HIV dementia, but they are a nonspecific finding.35,36 While CSF levels of monocyte chemoattractant protein-1 (MCP-1) correlate well with HIV
dementia in antiretroviral therapy–naive patients, MCP-1 levels do not correlate with neurologic impairment in treated patients.37
Markers of neuronal injury. In the HAART era, small studies suggest that neuronal proteins such as neurofilament (R. Price, unpublished data, 2006) and 14-3-3 protein may correlate with neurocognitive impairment in HIV-infected patients.38,39
Markers of oxidative stress. Good correlation in the earlier stages of HIV dementia is seen with levels of protein carbonyl40 and lipid peroxidation products.41 While these markers seem to be sensitive indicators of HIV dementia, they do not correlate with the severity of dementia. Thus, a combination of markers of neuronal injury and oxidative stress holds promise as a potential tool for following patients with HIV dementia; however, these tests are currently available only in research laboratories and need to be validated in larger populations.
Neuroimaging studies. Imaging studies are frequently used both to exclude CNS opportunistic processes and to identify the characteristic radiologic changes of HIV dementia. MRI demonstrates both cortical and central atrophy and characteristic confluent signal abnormalities within the deep white matter. These findings represent increased water content and can be reversed with effective antiretroviral therapy. However, atrophy and white matter abnormalities are generally not considered diagnostic, since they are also seen in 10% to 20% of neurologically normal seropositive patients (Figure 3).42 Furthermore, with the possible exception of the degree of caudate atrophy, these changes correlate poorly with dementia severity,43 although there is some evidence that white matter changes in HIV dementia patients may be reversed by effective antiretroviral therapy and that these changes may be associated with neurologic improvement.44
Profound cortical as well as subcortical atrophy, together with extensive confluent white matter abnormalities, are common features of
advanced dementia. Magnetic resonance spectroscopy shows increases in choline levels, which reflect astocytosis, and reductions in N-acetyl aspartate, which indicate neuronal injury. Brain metabolite levels correlate with various clinical and biochemical indices of neurologic progression in HIV-positive persons, such as severity of HIV dementia and CSF viral load in treatment-naive patients.45 Cerebral metabolite levels can normalize after 9 months of treatment with effective antiretroviral therapy, although the changes appear to lag behind improvements in CD4+ cell count and CSF HIV RNA levels.37
Among other advanced MRI techniques, diffusion tensor imaging, which probes microstructural changes in white matter, has demonstrated loss of fiber anisotropy
in normal-appearing white matter
in neurologically normal seropositive patients,46 while magnetization transfer contrast imaging reveals a significant reduction in the magnetization transfer ratio in white matter lesions, possibly reflecting gliosis.
SURVIVAL WITH HIV DEMENTIA
Without treatment, HIV dementia is rapidly progressive, with a mean survival of about 6 months—less than half of the average survival of patients with AIDS who do not have dementia.5,47,48 Patients may remain mildly demented and cognitively stable until death. This variability is in part dependent on the severity of immunodeficiency at the onset of dementia. Those with CD4+ cell counts of less than 100/µL progress more rapidly. Survival of patients has improved since the introduction of effective antiretroviral therapy.
COMORBIDITIES
There are several comorbidities that have an impact on the diagnosis and treatment of HIV dementia.
Drug Abuse
In certain cities around the world, injection drug use has reached epidemic proportions. Up to 30% of injection drug users are HIV-seropositive. Nearly half of the HIV-positive women in the United States contracted the infection via drug use. Furthermore, whereas rates of drug abuse fall off with age in the general HIV-seronegative population, this decline is not observed for HIV-seropositive adults, presumably because those persons who continue to use injection drugs continue to contract HIV at a steady rate.49 Those with
a history of injection drug use had more rapid neurologic progression.47
It is now apparent that compared with HIV-positive patients who do not use drugs, HIV-positive drug abusers have more rapid progression to more severe forms of neurocognitive dysfunction; in fact, some HIV-infected drug abusers may have an accelerated form of HIV dementia.50 However, currently there are no clinical or laboratory-based methods to distinguish HIV-mediated effects from drug abuse–mediated effects on the brain. Distinguishing between the two is important, because drug abuse–mediated damage is unlikely to respond to antiretroviral therapy, and neuroprotective strategies need to be developed for intervention in this group of patients.
Depression
Depression may be the initial presentation of HIV dementia and may be associated with the progression of cognitive impairment. Depression is common in patients with HIV infection and may be difficult to differentiate from HIV dementia, since HIV infection may precipitate similar symptoms, such as fatigue, pain, anorexia, and insomnia.51 It is common for depression to go unrecognized and untreated in patients with HIV infection; nevertheless, it may be associated with an increased mortality rate.52
Differentiating depression from HIV cognitive disturbance is difficult; some neuropsychological tests may help in differentiating patients with HIV cognitive impairment with and without depression.53 The relationship between HIV dementia and depression may be complex because both HIV infection and depression can affect the serotonergic system. Further, those patients who demonstrate depression and cognitive impairment together do not respond well to treatment.54
Coinfection With HCV
The prevalence of HIV/HCV coinfection is 15% to 30% in HIV-infected patients in the United States55,56 and may increase to 80% to 90% when patients with HIV are injection drug users. Recent studies have shown that HCV is neurotropic and can be found in macrophages within the brain.57 HCV can also be found in the CSF of patients coinfected with HIV and HCV.58-60 These patients also have greater cognitive impairment than do those infected with HIV alone.61 Chronic HCV infection may cause neuropsychological impairment without alterations of liver function62,63 and involves cognitive domains of attention, frontal executive function, and psychomotor speed.64,65 These impairments are independent of a history of injection drug use, depression, or fatigue. However, HCV infection alone usually is not sufficient to cause dementia. Patients coinfected with HIV and HCV present with worse cognitive dysfunction than do patients monoinfected with HIV or HCV.61,66 „
The effect of HCV infection on the progression of HIV disease is not clear. Studies directed at evaluating the effect of antiretroviral treatment and progression of HIV/HCV infection have shown that early antiretroviral treatment in HIV/HCV-coinfected patients may slow down liver fibrosis progression.67 However, in a longitudinal Italian seroconversion study of patients coinfected with HIV and HCV and a history of injection drug use, progression to AIDS was faster.68 HIV/HCV coinfection has become a treatment challenge, since HIV drugs are mainly metabolized in the liver, the target organ of HCV infection.
Aging
Aging—with all its comorbid factors, such as vascular disease, metabolic disturbances, and neurodegenerative diseases, superimposed on chronic HIV infection—presents a challenge to the diagnosis and treatment of HIV dementia.69 Several studies have shown that HIV dementia is more common in older patients with HIV infection,70-72 but these differences may be accounted for by age-related changes.71,73 The HIV Tat protein may contribute to these age-related changes by inhibiting the degradation or uptake of amyloid beta peptide, thus increasing the extracellular concentrations of this peptide.74-76
Aging is related to neurodegenerative diseases like Alzheimer disease. Amyloid deposition in the brain occurs with aging and is an important pathologic finding in Alzheimer disease. Amyloid beta peptide (ABP) is neurotoxic, and accumulation of this peptide in the brain has been implicated in the associ-ated neurodegeneration. Although the evidence for increased amyloid plaque formation in the brains of HIV-infected patients remains unsettled, ABP oligomers may be the
neurotoxic agent.77 Rempel and Pulliam74 found evidence of marked increases in diffuse amyloid plaques in HIV-infected brains compared with age-matched controls, while Gelman and Schuenke78 did not. Small sample sizes in each of the studies may account for the differences.
Pathophysiologic interactions between HIV and the mechanisms underlying Alzheimer disease could lead to accelerated and severe forms of dementia. Interactions between the two may occur at several levels. The apolipoprotein E4 (apoE4) allele has been implicated as a risk factor for both HIV dementia and Alzheimer disease.79 There is extensive literature demonstrating that both HIV-Tat protein and ABP can cause neurotoxicity. Further, Tat can directly interact with the low-density lipoprotein receptor and thus inhibit
the uptake of its ligands, including apoE4 and ABP.75 The cysteine-rich domain of Tat interacts with neprilysin. Neprilysin is a type II plasma membrane zinc metallopeptidase whose catalytic site resides outside of the cell, placing the enzyme in an ideal position to cleave secreted ABP. Cleavage of ABP by neprilysin represents a major mechanism for its clearance.80 Thus, inhibition of neprilysin activity could account for the increase in ABP levels.
A recent pathologic study suggested that prolonged antiretroviral therapy and aging may contribute to an overall increase in amyloid deposition, potentially mediated by inhibition of insulin degradation enzyme or disruption of the axonal transport of the amyloid precursor protein.81 These studies suggest that the diagnosis and treatment of HIV dementia may pose unique challenges in patients in whom these comorbidities are suspected.
Socioeconomic Impact of
HIV Dementia
HIV dementia, although a subcortical dementia, affects the performance and attention of infected patients and causes an eventual decline in their work performance and diminished levels of income. In the United States, disproportionately increasing numbers of women and minorities are
affected, and with associated poorer access to health care in communities that are disproportionately affected, patients are presenting in later stages of the illness.
Because HIV infection often strikes the population in the age group of 20 to 40 years, the socioeconomic impact of HIV dementia is predicted to be tremendous. These patients often lose their ability to earn a living and to drive and most often
require nursing home placement.82 Caregivers of patients with HIV dementia often experience both physical and mental health problems.83
TREATMENT
CSF-Penetrating
Antiretroviral Drugs
CSF-penetrating antiretroviral drugs are defined as those drugs with CSF concentrations (as determined by the median concentration from human studies) that exceed the level need-ed to inhibit replication of HIV (as determined by the median 50% inhibitory concentration in the ViroLogic PhenoSense Assay84). Specifically, these are stavudine, zidovudine, abacavir, efavirenz, nevirapine, and indinavir.85 At this point, it is not entirely clear what the optimum regimen is for treating HIV dementia. Recent data suggest that neurologic improvement is greater with the use of regimes that contain several drugs that potentially enter the CSF.86
Enhancement of Antiretroviral Drug Delivery to the Brain
Important factors that prevent antiretroviral drugs from entering into the brain include the active efflux of protease inhibitors by p-glycoprotein on brain endothelial cells.87 For the NRTI class, organic acid transport systems may mediate the penetration into the brain and CSF, although their clinical importance is undefined.88,89 Inhibitors of p-glycoprotein (eg, verapamil or nifedipine) and of organic acid transporters (uricosuric compounds such as the poorly tolerated probenecid or benzbromarone) are available but have not been tested in patients with HIV dementia.
Immune Reconstitution
Syndrome in CNS Following
Antiretroviral Therapy
Immune reconstitution inflammatory syndrome (IRIS) is a recently recognized clinical entity that results from the improvement of the immune system, generally a few weeks after the initiation of effective antiretroviral therapy.90 IRIS leads to an unexpected paradoxical deterioration of clinical status and is predominantly linked with a dramatic rise in CD4+ T-lymphocyte count and a lowering of HIV RNA viral level in the periphery. Although IRIS may result in improved control of an opportunistic infection or HIV replication itself, it also may be associated with a high degree of morbidity and mortality, particularly if it is untreated and affects the CNS.
Persons in whom an adverse clinical response is manifested following effective antiretroviral therapy will usually have a pathologic correlation of either worsening of the underlying infection or unmasking of a subclinical infection. IRIS can be attributable to any organ system but has only rarely been described involving the CNS. Patients who are antiretroviral-naive are particularly at risk for IRIS, irrespective of age
or baseline CD4+ cell counts.
Other risk factors include duration and extent of immunodeficiency, genetic susceptibility factors, and velocity of immune reconstitution.91 This is particularly important as antiretroviral therapy is becoming available to large numbers of persons worldwide.
Currently, no guidelines for prevention, diagnosis, or treatment of HIV dementia exist as it relates to IRIS in the CNS. IRIS in patients with HIV dementia has only recently been described in 2 patients whose conditions deteriorated following initiation of effective antiretroviral therapy, despite control of the virus in the periphery.
One of the patients died within a month of exacerbation of neurologic symptoms. The second patient had a more protracted course but died within 3 months of initiation of effective antiretroviral therapy with a progressive neurologic decline. At autopsy, these patients had T cells in perivascular regions and in the parenchyma. The T cells were immunostained for cytotoxic granules.92
We recently described another patient who had a more protracted course over several months and showed a partial response to corticosteroid treatment. These patients had prominent leukoencephalopathy on MRI scan that had some features similar to those seen in patients with progressive multifocal leukoencephalopathy, but JC virus could not be detected in either the CSF or the brain.93 Case reports of patients with vacuolar leukoencephalopathy have also been described, some of which have been attributed to an IRIS-like syndrome associated with effective antiretroviral therapy.94,95
Antiretroviral Considerations for Patients With HIV Infection and Cognitive Impairment
While it is well accepted that patients with HIV infection and cognitive impairment should be treated with antiretroviral drugs that have better penetration into the CNS,27,96 the use of effective antiretroviral therapy has posed new challenges. When faced with a patient whose plasma HIV level is well controlled but in whom cognitive impairment is developing and non–HIV-related causes have been excluded, the CSF HIV level should be determined. If the virus is detectable in the CSF, a change in the antiretroviral regimen is necessary.
Genotyping the virus in the CSF for drug-resistant mutants may be useful in determining which drugs to use. Independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of drug-resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation on failure of therapy.97
New Approaches to Treatment
of HIV-Related Cognitive
Impairment
Current approaches to antiretroviral therapy have targeted viral gene products. However, novel approaches are being developed that are directed against host genes involved in regulation of HIV replication. These include drugs such as minocycline, which suppresses activation of p38 mitogen-activated protein kinase pathways.98 In a macaque model, minocycline was shown to decrease viral replication, abolish neuroinflammation, and preserve neuronal morphology.98 Currently, a multicenter human clinical trial is under way. Low-dose valproate (500 mg/d or less) has been shown to have neuroprotective properties, and a small study suggested some benefit in patients with HIV dementia.99 This will now be explored in a larger clinical trial.
Another potential approach to treat HIV-related cognitive impairment is the use of anticancer drugs that exhibit anti-HIV activities. At least 4 chemically and pharmacologically distinct classes of anticancer drugs—certain cyclin-dependent kinase (CDK) inhibitors, topoisomerase 1 enzyme (top 1) inhibi-
tors, nonnucleoside antimetabolites, and estrogen receptor ligands—are promising candidates. These drugs are used at high doses for cancer therapy; at lower doses, they exhibit anti-HIV activity in vitro. The rationale that supports the development of these drugs is that HIV proteins such as Vpr and Tat perturb the cell cycle by acting on host factors such as cyclin/CDK complexes to optimize HIV replication. While the antiretroviral and anticancer activities of the CDK inhibitor flavopiridol appear to be mutually exclusive and unrelated in in vitro and animal models of HIV disease, the top 1 inhibitor 9-nitrocamptothecin, as well as the CDK inhibitor roscovitine, inhibits replication of HIV via selective sensitization of HIV-infected cells to apoptosis. This quality may lead to the eradication of proviral reservoirs, which is not accomplished by available antiretroviral drugs.100
The desired effects of roscovitine are at concentrations at which the drug does not cause antiproliferative effects (10 µM). This concentration is close to the nontoxic plasma concentrations in cancer patients.101 These approaches have a distinct advantage in that drug-resistant virus is unlikely to emerge and, hence, they potentially can be used early in the course of the illness and could therefore have an impact on the establishment of the viral reservoir in the brain.
Symptomatic Treatment
Proper treatment of neurologic symptoms can have a significant impact on the quality of life of patients. Below we have briefly discussed aspects of pharmacologic intervention that need special consideration in a patient with HIV dementia.
Psychosis or behavioral problems. Patients with HIV dementia are extremely susceptible to the adverse effects of psychoactive drugs, so the use of hypnotics and anxiolytics should be avoided.102,103 Atypical antipsychotics are the drugs of choice because of their selective action on D3 and D4 receptors.104 However, olanzapine is metabolized primarily by CYP1A2 and glucuronosyl transferases, both of which are induced
by the HIV protease inhibitor ritonavir. Hence, higher doses of olanzapine may be needed if administered with other liver enzyme–inducing agents.105 Small doses of neuroleptics, such as haloperidol, 0.5 mg, may be needed in the agitated or combative patient.
Depression. Depression frequently accompanies HIV infection and can have a major impact on the quality of life of the patients.106 If marked inertia is present, selective serotonin reuptake inhibitors such as fluoxetine in doses 25% to 50% of the usual dose or methylphenidate can be tried. Tricyclic antidepressants may precipitate delirium because of their anticholinergic effect, and if they are used, serum levels should be monitored frequently.
Seizures. Seizures may occur in some patients as a result of HIV infection alone.107 Levetiracetam, gabapentin, tigabine, and topiramate are the preferred anticonvulsants because of their lack of drug-drug interactions and lack of effect on the cytochrome P-450 system.108 While low-dose valproate may be neuroprotective, anticonvulsant doses of valproate should be particularly avoided because in vitro studies suggest that it can induce viral replication at higher doses.109 It also has effects on cytochrome P-450.110
Headaches. Intractable vascular headaches may develop in some patients with HIV infection. Initial treatment should include migraine prophylaxis.111 Triptans should be used cautiously because of interactions with protease inhibitors. Nonresponders may require treatment with opiates.
Parkinsonism. Since HIV infects the basal ganglia, akinetic parkinsonism with bradykinesia and postural instability may occur.103 Dopamine agonists may be used in patients in whom parkinsonism is manifested; however, the response is usually poor.103
Sleep disturbances. A variety of sleep abnormalities may occur in patients with HIV infection as a result of causes which may include pain-ful peripheral neuropathies that respond to adequate control of pain and112 sleep apnea from lipodystrophy due to use of protease inhibitors.116 Insomnia may also be caused by efavirenz use.114,115
OTHER CONSIDERATIONS
Medicolegal Issues
In patients with progressive dementia, medicolegal issues should be discussed at any early stage, before HIV dementia becomes too severe. These issues include establishment of a power of attorney, completion of a living will, and arrangement for the dispersal of assets.
Driving
HIV-positive neurophysiologically impaired persons are at increased risk for driving impairments. Where available, simulator testing may help identify driving-impaired persons.116
CONCLUSION
The treating physician faces new challenges in the management of the neurologic manifestations of HIV infection in the HAART era. The recent recognition of new neurologic syndromes and the frequent occurrence of comorbidities require careful investigation of the patient’s condition. Careful consideration is necessary in the choice of antiretroviral drugs for management of a patient with HIV dementia, and once the treatment has been initiated, patients must be carefully monitored for potential side effects and complications of treatment. Quality of life for these patients can also be affected by symptomatic treatment of some of the neurologic manifestations and management of the psychosocial aspects of HIV dementia. h

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